Wednesday, February 25, 2015

Cablevision Seems Quite Smart

As a Cablevision customer there were times I had my doubts. I even had doubts that a CATV company could execute a WiFi system. But Cablevision has exceeded all doubts. They are quite smart in deploying WiFi.

About 10 years ago we tried a mesh WiFi system we called Linear A. It used a modified Roof Net software developed by MIT grad students who went on to found a Google funded start up called Meraki. It was sold to Cisco. But the bottom line was that mesh WiFi works. Make each customers cable modem a Meshed Wifi and you suddenly get a powerful system. I use Cablevision's WiFi as I come home from the City, one train stop after the other. Cheaper than any Verizon service.

In all, this meshed distributed approach has great potential.  If Cablevision can execute this as well as it had its fiber backbone and WiFi network, then I believe it could be a real threat to major urban users.
In 2006-2009 we deployed many of these mesh units but the problem was that there were few dual mode sets, only cellular air interfaces. Now WiFi air interfaces are exploding.

As they state in Fierce Wireless:

Just weeks after launching its low-cost Freewheel Wi-Fi calling and data service, Cablevision.... told investors during the company's fourth quarter earnings call that he believes Freewheel will disrupt the cellular industry and his company is going to put more emphasis on its Wi-Fi initiatives.  Specifically, ... said that his company is going to prioritize Wi-Fi over the company's traditional video business, which is facing rising programming costs. He noted that margins for data products such as Wi-Fi are increasing. Although ... admitted that it was too early to assess demand for Freewheel, he said that the company is seeing usage outside its footprint primarily by non-U.S. citizens who want a low-cost phone available for when they conduct American business.

 Frankly, this is just a great idea, whose time has come. Cablevision has shown both interest and competence and it will be interesting to see how they execute on this. Unlike a Google approach, spend billions and make lots of noise, Cablevision just moves ahead elegantly and with great promise.

Now It's Oatmeal!

There is a report in Eureka linking a mold on oats to renal cancer. They state:

some oat-based breakfast cereals in the U.S. contain a mold-related toxin called ochratoxin A (OTA) that's been linked to kidney cancer in animal studies. The findings could have implications for consumer health. 

 The article states:

Ochratoxin A (OTA) has been found in all major cereal grains including oat, wheat, and barley worldwide and considered as a potential concern in food safety. A total of 489 samples of corn-, rice-, wheat-, and oat-based breakfast cereal were collected from U.S. retail marketplaces over a two-year period, and OTA was determined by high-performance liquid chromatography. Overall, 205 samples (42%) were contaminated with OTA in the range from 0.10 to 9.30 ng/g. The levels OTA were mostly below of the European Commission Regulation (3 ng/g) except in 16 samples of oat-based cereals. The incidence of OTA was highest in oat-based breakfast cereals (70%, 142/203), followed by wheat-based (32%, 38/117), corn-based (15%, 15/103), and rice-based breakfast cereals (15%, 10/66). On the basis of the incidence and concentration of OTA, oats and oat-based products may need greater attention in further surveillance programs and development of intervention strategies to reduce health risks in consumers.

 Molds are well known toxins and causes of a variety of cancers. The presence of this molecule in uncooked oats may or may not be significant but in processed oat cereals which are eaten uncooked is a concern. Especially since there is a strong push to eat oats to manage cholesterol.

Eureka continues:

Animals exposed to OTA in experiments developed kidney tumors. Although the U.S. doesn't currently regulate the contaminant, the European Union has set maximum limits for OTA in food. 

This may become a major FDA issue especially since the EU regulators have chimed in.

Monday, February 23, 2015

Oops! Guess I was Right

Looks like after the USPTF issued their "brilliant" dictum of not doing PSA tests that the result is more aggressive PCa and more dead men! Told Ya! Never trust a Government Panel, been there and saw what they do.

Now Healio describes the increase in PCa. As the piece states:

The US Preventive Services Task Force recommends against routine-based PSA prostate cancer screening for healthy men regardless of age. In 2009, the USPSTF issued that recommendation for men aged 75 years or older. In 2011, the task force issued draft guidance expanding that recommendation to include all men, and it finalized that recommendation in May 2012. A study by ...and colleagues was the first to measure changes in prostate cancer presentation since the USPSTF made these recommendations. “If you don’t screen the people, then when they do show up with prostate cancer, the horse is out of the barn,” ...said during a press conference. “They’re more likely to be at intermediate risk because, by missing early disease, then you are going to catch it when it’s palpable or causing symptoms. That, of course, makes it much more difficult to treat.”

We stated this at the time of the USPTF report. We provided detailed evidence of the contrary of the re[port. We demonstrated that the two NEJM studies were flawed. But think of all the PSA tests it saved. Then think of all the bone mets and DICs resulting. But then again we have our beloved GS9s and subsidized Government cafeterias... Welcome to the ACA, and we have not yet gotten to those "death panels". or have we?

Medicare and Obesity

The ACA has allowed Primary Care physicians to get fully reimbursed for counselling Medicare Patients who are obese. Kaiser has a piece discussing its lack of success. They state:

For older adults, being mildly overweight causes little harm, physicians say. But too much weight is especially hazardous for an aging body: Obesity increases inflammation, exacerbates bone and muscle loss and significantly raises the risk of heart disease, stroke, and diabetes....o help the 13 million obese seniors in the U.S., the Affordable Care Act included a new Medicare benefit offering face-to-face weight-loss counseling in primary care doctors’ offices. Doctors are paid to provide the service, which is free to obese patients , with no co-pay. But only 50,000 seniors participated in 2013, the latest year for which data is available....who is obese herself, says she doesn’t expect her older patients to lose a lot of weight. “I think you’ll see weight loss of 10 to 20 pounds, but whether you’re going to see people lose 50 to 100 pounds as they’re older, I doubt it.”. Still, ... says, even with small amounts of weight loss in her older patients, she expects to see a decrease in the complications of chronic medical diseases, including diabetes-related leg amputations.

The facts are:

1. Obesity is an inflammatory enhancing state. Inflammation enhances the potential for and the exacerbation of various cancers.

2. Ongoing obesity has multiple sequella including costly kidney and cardiovascular problems.

3. Yes, Primary Care physicians have problems communicating with patients and worse patients just do not listen. Look at the number, 13 million obese Medicare patients and only 50,000 were dealt with, not necessarily successfully.

 The problem of obesity starts young and then continues. Why not stop it in the teenage years? Why not before 40? Why wait until 65 and later. The costs of obesity on future generations will be explosive. The ACA may have had good intentions but adherence demands perhaps a heavy hand.

Sunday, February 22, 2015

The End of an Era

I got a note today from COMSAT alumni that they are finally removing the 32 m antenna AND-03 at the old Andover Earth Station. I used that antenna to connect to European stations using the above antenna in the 70s to monitor Soviet Nuclear Weapons tests.

This is the end of an era. The old 4/6 GHz bands no longer serve the original purpose. COMSAT was an interesting company, an evolution from a Government vision for satellite communications, managed by a collection of DoD types which lost sight of the commercial world and was slowly disassembled into nothing.

It was a great training ground to understand Washington...pure ruthless politics...played just for the sake of the game. Amazing what a monopoly can do...then it dies.

Friday, February 20, 2015

Telling Us the Obvious

From the Office of Disease Prevention and Health Promotion comes this years guidelines. First off the name of this institution is right out of 1984 or the like. We have a group of folks sitting around on an annual basis telling us what to eat. The answer is simple, less. We are in generally too fat, too lazy, and costing the health care system too much. End of report. But no, it is our Government at work and they cannot say in a few words what they can spend tens of thousands on. You have to read this report.

For example they state:

The 2015 DGAC’s work was guided by two fundamental realities. First, about half of all American adults—117 million individuals—have one or more preventable, chronic diseases, and about two-thirds of U.S. adults—nearly 155 million individuals—are overweight or obese. These conditions have been highly prevalent for more than two decades. Poor dietary patterns, overconsumption of calories, and physical inactivity directly contribute to these disorders. Second, individual nutrition and physical activity behaviors and other health-related lifestyle behaviors are strongly influenced by personal, social, organizational, and environmental contexts and systems. Positive changes in individual diet and physical activity behaviors, and in the environmental contexts and systems that affect them, could substantially improve health outcomes.

 So what is new with any of this? Nothing. Yet the problem is solved by individual choice. Yes, if we burn 2000 kcal per day we better not eat 2100 kcal per day. 3500 kcal is one added pound. Been that way for a few centuries at least.

They continue:

The DGAC found that several nutrients are underconsumed relative to the Estimated Average Requirement or Adequate Intake levels set by the Institute of Medicine (IOM) and the Committee characterized these as shortfall nutrients: vitamin A, vitamin D, vitamin E, vitamin C, folate, calcium, magnesium, fiber, and potassium. For adolescent and premenopausal females, iron also is a shortfall nutrient. Of the shortfall nutrients, calcium, vitamin D, fiber, and potassium also are classified as nutrients of public health concern because their underconsumption has been linked in the scientific literature to adverse health outcomes. Iron is included as a shortfall nutrient of public health concern for adolescent females and adult females who are premenopausal due to the increased risk of iron-deficiency in these groups. The DGAC also found that two nutrients—sodium and saturated fat—are overconsumed by the U.S. population relative to the Tolerable Upper Intake Level set by the IOM or other maximal standard and that the overconsumption poses health risks.

Any reasonable diet would overcome this. Eating fast foods will not. Again nothing new here.

The report them bemoans:

Obesity and many other health conditions with a nutritional origin are highly prevalent. The Nation must accelerate progress toward reducing the incidence and prevalence of overweight and obesity and chronic disease risk across the U.S. population throughout the lifespan and reduce the disparities in obesity and chronic disease rates that exist in the United States for certain ethnic and racial groups and for those with lower incomes.  

Again, and for centuries, one knows that input less output is net accumulation. Added weight, above BMI 25 means increase inflammation, increased inflammation increases the risks of cancer, such as breast and prostate. We know that. So how does one regulate this? Simple, tax weight. Too simple, we become anti obese, yes, because it is to societies benefit. If one wants to be that way then one must carry the costs of being so. At least in a fair market.

They conclude:

It will take concerted, bold actions on the part of individuals, families, communities, industry, and government to achieve and maintain the healthy diet patterns and the levels of physical activity needed to promote the health of the U.S. population. These actions will require a paradigm shift to an environment in which population health is a national priority and where individuals and organizations, private business, and communities work together to achieve a population-wide “culture of health” in which healthy lifestyle choices are easy, accessible, affordable, and normative—both at home and away from home. In such a culture, health care and public health professionals also would embrace a new leadership role in prevention, convey the importance of lifestyle behavior change to their patients/clients, set standards for prevention in their own facilities, and help patients/clients in accessing evidence-based and effective nutrition and comprehensive lifestyle services and programs.

Nonsense! It does not take bold actions. Just put the fork down! The Government has de minimis role, since Government education programs are poor in influencing the public. The only factor is charging for obesity. Frankly there is no other way. It worked on tobacco!

The Government and Its Own Laws

In the NY Times today is a piece about CMS sending out erroneous tax filing data. Surprise? Not really. Take Ginnie Mae in HUD. Despite the law requiring sending 1099s by February 14th, do not count on HUD sending anything on time! It is the Government, most likely one of the worst organizations known to man. One should read de Tocqueville's work on The French Revolution. He alleges the cause was the incompetent centralization of the governance of France by the administration in Paris. Centralized and overpowering.

The Times notes:

About 800,000 taxpayers who enrolled in insurance policies through received erroneous tax information from the government, and were urged on Friday to hold off on filing tax returns until the error could be corrected. The ... administration, under heavy pressure from congressional Democrats, also announced that it would give several million people more time to buy health insurance so they could comply with federal law and avoid tax penalties. The incorrect insurance information is used in computing taxes. Consumers can expect to receive corrected data in the first week of March. With the new data, officials warned, some taxpayers will owe more and some will owe less. Officials said they did not know why the error had occurred.

Is this a surprise, No.  But after all, Officials did not know how it happened. Would one ever think to check.

For those seeking Government controlled Health Care, please just think about it. Remember its the same GS9 who did this one who will mandate your cancer coverage. Hope they don't make the decision on their way to a doughnut break!

A Greek Marxist

Yanis Varoufakis has written a piece that appeared in the Guardian recounting his Marxist views and their relevance in today’s economic climate[1]. I will try to recount some of his observations as they also lend a light upon the current Greek crisis. Greece is a challenging country. I had a company there once and unlike any of my other companies could never seem to get it started. There was one bureaucratic roadblock after another, one reason for delay, one need for another person, added space, and more time. Greece was and is fundamentally dysfunctional. This is quite strange because the Greeks outside of Greece are very entrepreneurial, very productive, and very successful. Thus one may ask; what does the Greek peninsula do to falter basic Greek capabilities?

Let us examine Varoufakis and his journey with Marx. He states:

My view on this dilemma has always been that the powers that be are never perturbed by theories that embark from assumptions different to their own. The only thing that can destabilize and genuinely challenge mainstream, neoclassical economists is the demonstration of the internal inconsistency of their own models. It was for this reason that, from the very beginning, I chose to delve into the guts of neoclassical theory and to spend next to no energy trying to develop alternative, Marxist models of capitalism. My reasons, I submit, were quite Marxist.

His argument is that capitalism is flawed and to demonstrate this fundamental flaw and to demonstrate it is necessary not to examine and defend Marx but to examine and explain the flaws of capitalism itself, many which he claims are self-evident from the current crisis.

He sees the Marxist world as did Marx, and he recounts it as follows:

Marx created a narrative populated by workers, capitalists, officials and scientists who were history’s dramatis personae. They struggled to harness reason and science in the context of empowering humanity while, contrary to their intentions, unleashing demonic forces that usurped and subverted their own freedom and humanity.

The Marxist view of the existence of disparate but well defined “groups” rather than individuals was a means to explain the basis for the ultimate clash via his dialectic process. He continues with his dialectic understanding by stating:

This dialectical perspective, where everything is pregnant with its opposite, and the eager eye with which Marx discerned the potential for change in what seemed to be the most unchanging of social structures, helped me to grasp the great contradictions of the capitalist era. It dissolved the paradox of an age that generated the most remarkable wealth and, in the same breath, the most conspicuous poverty. Today, turning to the European crisis, the crisis in the United States and the long-term stagnation of Japanese capitalism, most commentators fail to appreciate the dialectical process under their nose. They recognize the mountain of debts and banking losses but neglect the opposite side of the same coin: the mountain of idle savings that are “frozen” by fear and thus fail to convert into productive investments. A Marxist alertness to binary oppositions might have opened their eyes.

Here he posits some Marxist opposition yet he is near impossible to follow as to just what that binary opposition is. The US economic problems are fundamentally political and secondarily structural. The core to the collapse in 2008 was a result of political changes in the late 1990s as well as accomplices in Government who facilitated and then protected those whose actions led to the collapse. One must recall that it was the Government housing agencies which led the way with overextending in real estate and that were Government action and not a rational market response.

The Marxist view of anti-individualism, the existence and commonality of labor, may have had validity in the 19th Century but the core changes in the economy today are fundamentally driven by the destruction of that commonality. Production line workers are replaced by robots, the ultimate Marxist proletariat. Technology is fundamentally individual but it requires effort, more effort than just “showing up” at the assembly line. He continues:

Both electricity and labour can be thought of as commodities. Indeed, both employers and workers struggle to commodify labour. Employers use all their ingenuity, and that of their HR management minions, to quantify measure and homogenize labour. Meanwhile, prospective employees go through the wringer in an anxious attempt to commodify their labour power, to write and rewrite their CVs in order to portray themselves as purveyors of quantifiable labour units. And there’s the rub. If workers and employers ever succeed in commodifying labour fully, capitalism will perish. This is an insight without which capitalism’s tendency to generate crises can never be fully grasped and, also, an insight that no one has access to without some exposure to Marx’s thought.

His observation above is of merit. Indeed one sees new workers trying to seek employment by commoditizing themselves as what they perceive are interchangeable units of production. In reality business needs flexible and creative workers. I have often said and have often acted upon the selection of a good High School grad versus a University post grad. It is essential in today’s world to have an employee who can adapt rather than conform. That being so, the concept flies in the face of Marx.

The author continues:

If capital ever succeeds in quantifying, and subsequently fully commodifying, labour, as it is constantly trying to, it will also squeeze that indeterminate, recalcitrant human freedom from within labour that allows for the generation of value. Marx’s brilliant insight into the essence of capitalist crises was precisely this: the greater capitalism’s success in turning labour into a commodity the less the value of each unit of output it generates, the lower the profit rate and, ultimately, the nearer the next recession of the economy as a system. The portrayal of human freedom as an economic category is unique in Marx, making possible a distinctively dramatic and analytically astute interpretation of capitalism’s propensity to snatch recession, even depression, from the jaws of growth.

Somehow he sees this power of “capital” and its control over “labor” as the ultimate Marxist dialectic. That view is in sharp contrast to the changing reality of the evolving entrepreneurial world. Greeks leave Greece and prosper by adapting, by being individuals, not by being cogs. In Greece, so many line-up at the dole of Government jobs, lack creativity, and become the Marxist pool of labor.

He then discusses the issue of markets. Namely “markets” as a mechanism to deal with everything in our daily lives from health care to pollution control. He states:

In his recent book Never Let a Serious Crisis Go to Waste, the historian of economic thought, Philip Mirowski, has highlighted the neoliberals’ success in convincing a large array of people that markets are not just a useful means to an end but also an end in themselves. According to this view, while collective action and public institutions are never able to “get it right”, the unfettered operations of decentralized private interest are guaranteed to produce not only the right outcomes but also the right desires, character, ethos even. The best example of this form of neoliberal crassness is, of course, the debate on how to deal with climate change. Neoliberals have rushed in to argue that, if anything is to be done, it must take the form of creating a quasi-market for “bads” (eg an emissions trading scheme), since only markets “know” how to price goods and bads appropriately. To understand why such a quasi-market solution is bound to fail and, more importantly, where the motivation comes from for such “solutions”, one can do much worse than to become acquainted with the logic of capital accumulation that Marx outlined and the Polish economist Michal Kalecki adapted to a world ruled by networked oligopolies.
Neoliberals have rushed in with quasi-market responses to climate change, such as emissions trading schemes.

Indeed markets have limits, and sometimes economists tend to value them where they really do not belong. Take the market mechanism to control pollution or carbon emissions. Frankly, if it is a problem, then the solution is technical, not political, that is a “market” solution. All too often these “market” solutions are euphemisms for political beliefs. A prime example is the Pigou tax. Some neo-liberal economists are enamored with them. They see them as a fancy and efficient way to control a perceived problem. In fact if it is a technical problem, carbon gas, then the solution must be a technical one, not a political one.

Finally he makes some interesting remarks as to the mathematical characterization of economics.

Why did Marx not recognize that no truth about capitalism can ever spring out of any mathematical model? If I am right, Marx knew what he was doing. He understood, or had the capacity to know, that a comprehensive theory of value cannot be accommodated within a mathematical model of a dynamic capitalist economy. He was, I have no doubt, aware that a proper economic theory must respect the idea that the rules of the undetermined are themselves undetermined. In economic terms this meant a recognition that the market power, and thus the profitability, of capitalists was not necessarily reducible to their capacity to extract labour from employees; that some capitalists can extract more from a given pool of labour or from a given community of consumers for reasons that are external to Marx’s own theory.

Indeed, mathematical models in economics work if they are ex post facto accounting models, dealing with tautological facts, but all too often stretch the slightest truth when they prognosticate.

As a closing statement he appeals to the perceived loss of human equality. He bases that view on the following observation:

My personal nadir came at an airport. Some moneyed outfit had invited me to give a keynote speech on the European crisis and had forked out the ludicrous sum necessary to buy me a first-class ticket. On my way back home, tired and with several flights under my belt, I was making my way past the long queue of economy passengers, to get to my gate. Suddenly I noticed, with horror, how easy it was for my mind to be infected with the sense that I was entitled to bypass the hoi polloi. I realized how readily I could forget that which my leftwing mind had always known: that nothing succeeds in reproducing itself better than a false sense of entitlement. Forging alliances with reactionary forces, as I think we should do to stabilize Europe today, brings us up against the risk of becoming co-opted, of shedding our radicalism through the warm glow of having “arrived” in the corridors of power.

Instead of bemoaning his failure to be with the masses, he should be happy that the masses have the ability to travel. The economic messes we have, albeit shabby at times, have actually enabled the masses to live better lives and enjoy a modicum of equality amongst the power elite.

Genetic Testing

The FDA has given approval to 23andMe for its genetic tests under a 510K ruling. They state:

The U.S. Food and Drug Administration today authorized for marketing 23andMe’s Bloom Syndrome carrier test, a direct-to-consumer (DTC) genetic test to determine whether a healthy person has a variant in a gene that could lead to their offspring inheriting the serious disorder. Along with this authorization, the FDA is also classifying carrier screening tests as class II. In addition, the FDA intends to exempt these devices from FDA premarket review. The agency plans to issue a notice that announces the intent to exempt these tests and that provides a 30-day period for public comment. This action creates the least burdensome regulatory path for autosomal recessive carrier screening tests with similar uses to enter the market.

In addition they also specifically stated:

“The FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information. Today’s authorization and accompanying classification, along with FDA’s intent to exempt these devices from FDA premarket review, supports innovation and will ultimately benefit consumers,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “These tests have the potential to provide people with information about possible mutations in their genes that could be passed on to their children.”

The problem is that consumers would generally have no clue as how to interpret the results and even more so most physicians would be equally at a loss.

Certain genetic markers are definitive and others are suggestive. How is a consumer to understand that? This may present a substantial challenge to the health care system.

Thursday, February 19, 2015

Shoveling Snow

In the NY Times there is a piece on how our towns have managed to clamp down on any individual spirit. When I was a young man I sold Christmas Cards in July, had a paper rout of 112 customers spread over some 8 miles, mowed lawns, shoveled snow, and other similar tasks. I learned a great deal from the process and never once did a NYC Police Officer approach me for what I was doing, other than my father just to make sure I got an opportunity to do more!

But alas, in our new Mommy State, yes in New Jersey, you need a permit to ask to shovel snow. Yes folks, a permit, at the cost of $200! You cannot make this up. Frankly this shows we have too much Government, if they have time to spend on this issue. But wait, it gets worse. They even dispatched the Police to send the young snow shovelers a packing! This is New Jersey, not Berkeley, not Burlington VT. It is the Soprano's State! People have just too much spare time.

As the Times records;

Armed with about 100 fliers, ...., both 18 and seniors at .....High School, went door to door in ..., N.J., and then headed to ..., a neighboring town of about 10,000, to offer snow-shoveling services for a reasonable price the following day. The ensuing combination of neighborhood vigilance, community policing, social media, local and national news coverage, libertarian ideology and the New Jersey Legislature swirled into an unexpected narrative about small-town living, or media fishbowls, or perhaps snowstorms. After handing out about 40 fliers with their names and cellphone numbers, around 5:45 p.m. on Jan. 27, the two teenagers were stopped by police officers responding to a call that some suspicious characters were traipsing through yards, going door to door. ... met the description and were told that soliciting without a permit was “technically illegal” according to a town ordinance, .... said. They were also violating the town’s travel ban, which had gone into effect at 5 p.m., six hours before the state’s.

 Yep, the town sent a car with Police to scatter the wandering snow shovelers. Now how much did that dispatch cost the town? I have seen bullet holes, smashed mail boxes, vandalism, and the like that at best gets a Police report but in my experience never an investigation. But go outside to make a few dollars and the hounds of Hell descend.

Metformin and Statins

Prostate cancer has frequently been seen related to inflammatory processes. The exact connection is yet to be determined. However recent results have indicated that metformin has shown some effect on PCa and a recent paper by Danzig et al shows significant effects with metformin and statins. Both drugs have a certain antiinflammatory role, one in glucose metabolism management and the other through lipid pathways. In this paper we examine both the Danzig et al results as well and the details regarding the specific pathways involved. Specifically the drugs deal with metabolic related pathways, which is no surprise given the nature of Type 2 Diabetes. However the statin usage is not directly metabolic but may very well be so. In a recent White Paper we expand upon the results, summarized herein.

Shao et al state[1]:

The widely used anti-diabetic drug metformin has been shown to exert strong antineoplastic actions in numerous tumor types, including prostate cancer (PCa). In this study, we show that BI2536, a specific Plk1 inhibitor, acted synergistically with metformin in inhibiting PCa cell proliferation. Furthermore, we also provide evidence that Plk1 inhibition makes PCa cells carrying WT p53 much more sensitive to low-dose metformin treatment. Mechanistically, we found that co-treatment with BI2536 and metformin induced p53-dependent apoptosis and further activated the p53/Redd-1 pathway.

Moreover, we also show that BI2536 treatment inhibited metformin-induced glycolysis and glutamine anaplerosis, both of which are survival responses of cells against mitochondrial poisons. Finally, we confirmed the cell-based observations using both cultured cell-derived and patient-derived xenograft studies. Collectively, our findings support another promising therapeutic strategy by combining two well tolerated drugs against PCa proliferation and the progression of androgen-dependent PCa to the castration-resistant stage.

For example in the work of Margel et al they note:

By using fractional polynomials, we verified that the association between cumulative metformin use after PC diagnosis and PC specific mortality is linear. Onmultivariable analysis, for each additional 6 months of metformin use after PC diagnosis, there was a 24% reduction in PC-specific mortality (adjusted HR [aHR], 0.76; 95% CI, 0.64 to 0.89). Increasing durations of cumulative use of all other antidiabetic medications was not associated with PC-specific mortality.

In a similar manner in a study with statins Allott et al noted[2]:

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomized controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

Thus it would be reasonable to try an analysis with metformin and a statin combined. It is this study that we have focused upon as a vehicle to explore the effects on prostate cells using drugs that have effects on processes which are fundamentally inflammatory; excess blood glucose and excess blood lipids. To do this we sue the most recent paper of Danzig et al where they state:

The combination of statins and metformin in men undergoing RP for prostate cancer (PCa) may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship.

Thus there may very well be a beneficial result of such an approach. We briefly examine this and the details beneath in terms of the cellular pathway dynamics. In this analysis we utilize the Danzig et al paper and examinie in some details the functions of the specific drugs and their pathway characteristics. We specifically focus on metabolic pathway elements such as mTOR, AMPK, and how these are influencing a pathogenic characteristic leading to PCa.

Our focus is on the results from the Danzig et al paper. It demonstrates a synergism between metformin and statins in reducing mortality from both HGPIN and PCa. The issue of concern is; just how do these two medications function and what if anything can be generalized from this observation? It is well known that statins have an ameliorative effect on certain cancers and it is also well known that cancers can be initiated and exacerbated by inflammatory processes such as Type 2 Diabetes. We examine some of the basic observations presented in the paper and then proceed to examine the details of the pathway controls.

From the Dantzig paper we have the following survival across the four groups:

Note the alleged improvement. Also presented in the paper are Hazard Ratios. We summarize three key ones below.

First, we summarize the results of Hazard Ratios on several key factors in the initial stages of presentation. These are all related to biochemical recurrence, BCR.

Second the Hazard Ratios for race are presented. Surprisingly Asia is higher than African American.

Third, below is the Hazard Ratio summary for conditions of the lesion. What is interesting is the importance of pre-operative PSA levels. Perhaps this is a marker for reflecting on the importance of continuing to measure PSAs since the higher it is pre-operatively the greater the chance of post-operative recurrence.

As Danzig et al conclude:

In conclusion, we found that the combination of statins and metformin in men undergoing RP for PCa may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship. Finally, continued research into the molecular mechanisms by which these drugs affect cancer behavior will be highly instructive.

Thus the study presents some significant additional insight into pathways via the use of these medications. We thus start with pathways and then consider the effects of the medications.

Now metabolic factors in a cells environment place stress upon a cell that can result in loss of control as shown above. One metabolic or environmental factor is inflammation, others such as excess glucose or loss of glucose control is another. We examine the latter here.

For example, regulating p53 expression is known to be a major goal. Loss of that regulation is a major concern. One of the major players in that role is AMPK, AMP kinase. AMPK is a metabolic regulatory gene product that on the one hand manages cell energy control and on the other hand can control p53. Thus controlling this element is essential.

This then leads us to other gene products such as mTOR and essential metabolic gene product as well as LKB1.

Cell metabolism is the process whereby a cell uses energy that is made available to it to maintain normal processes and to grow and reproduce as may be required. Normal metabolic processes in a cell allow for the control of all of the elements in a balanced manner. Excess glucose as seen in Type 2 Diabetes can result in quasi-inflammatory states and loss of homeostasis.

Let us focus briefly upon AMPK, AMP kinase, as an initial point to understand the intra-cellular metabolic processes. AMPK is a key control element in many intracellular pathways[3].

From the paper by Mihaylova and Shaw we have[4]:

One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases.

AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. Here we review a number of recent breakthroughs in the mechanistic understanding of AMPK function, focusing on a number of newly identified downstream effectors of AMPK.

From the work of Shackelford and Shaw we have[5]:

In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity.

LKB1 encodes a serine–threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes.

The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.

In particular Shackelford and Shaw demonstrate the impact of Metformin on this pathway.

As Mendelsohn et al state:

While growth factor–stimulated signaling cascades promote cell growth under favorable conditions, cells have sophisticated nutrient sensing systems that serve to block growth when the internal energy supply is limiting. These regulators ensure that, during periods of intracellular nutrient depletion, metabolites are redirected from anabolic pathways and instead used to fuel catabolic pathways that will provide the energy required to survive the period of nutrient limitation. The AMP-activated protein kinase (AMPK) plays a major role coordinating cellular energy status with appropriate metabolic responses.

AMPK directly senses cellular energy levels in the form of the AMP/ATP ratio. Falling energy levels increase the cellular AMP/ATP ratio, priming AMPK for activation by the liver kinase B1 (LKB1). AMPK phosphorylates multiple targets with the cumulative effect of blocking anabolic reactions and stimulating energy-generating catabolic pathways.

For example, AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), with the dual effect of blocking fatty acid synthesis and activating fatty acid oxidation. AMPK also directly inhibits cell growth, both by inducing a p53-dependent cell cycle arrest and by blocking mTOR activity at multiple levels. Through these diverse activities, AMPK functions as a metabolic checkpoint, ensuring that cell growth is halted until bioenergetic conditions are favorable for growth.

AMPK is a powerful regulator of cell dynamics. It senses and manages energy via the ATP control cycle. Its impact on p53 which we have discussed earlier is also a major factor which may lead to cell oncogenesis. Thus examining how AMPK reacts to excess glucose and how it can be reset is a key observation.

mTOR is a control protein that in involved in metabolic related pathways. mTOR, the mammalian target of rapamycin, is a gene product (1p36.2) is a protein which acts in a critical manner in interconnecting the genetic circuits in mammals, and especially man. It fundamentally controls glucose transport and protein synthesis. The pathway depicted below is a modification of the graphic from Weinberg (p 785) which shows mTOR in its two modes, one with Raptor assisting and one with Rictor. The Rictor/mTOR mode activates the Akt pathway via the placement of a phosphate and this manages the protein synthesis portion. The inclusion of rapamycin will block the Raptor/mTOR path and reduce the protein synthesis and cell growth portion. The inhibitory effect on Akt/PKB by rapamycin is assumed to be the main factor in its anti-cancer effects.

We depict the mTOR C1 pathway below:

The following chart presents a more complex version of the mTOR C1 pathway (Raptor). This allows us to best understand the complex interactions. The mTOR C1 and C2 pathways are depicted in the combined chart below:

Looking at the complexity of the mTOR pathway it presents an interesting one for addressing PCa. Kinkaide et al (2008) indicate:

Among the major signaling networks that have been implicated in advanced prostate cancer are the AKT/mammalian target of rapamycin (AKT/mTOR) and MAPK pathways. Indeed, deregulated expression and/or mutations of the phosphate and tensin homolog tumor suppressor gene (PTEN) occur with high frequency in prostate cancer, leading to aberrant activation of AKT kinase activity as well as its downstream effectors, including the mTOR signaling pathway. In addition, many prostate tumors display deregulated growth factor signaling, which may result in activation of MAPK kinase 1 (MEK) kinase and ultimately ERK MAP.

Notably, previous studies have demonstrated that the AKT/mTOR and MAPK signaling pathways are alternatively and/ or coordinately expressed in advanced prostate cancer and function cooperatively to promote tumor growth and the emergence of hormone- refractory disease. These observations formed the basis for our hypothesis that targeting these signaling pathways combinatorially may be effective for inhibiting tumorigenicity and androgen independence in prostate cancer.

Kinkaide et al also demonstrate the creation of HGPIN via their work. This represents another pathway of HGPIN to PCa.

LoPiccolo et al state:

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers.

As we have shown with the more complex Weinberg model, here mTOR and PTEN play a strong role in the overall control. The authors show the points of possible control. The complexity of the pathways will be a challenge. It is less an issue of size complexity than a feedback and instability complexity. Nelson et al (2007) have demonstrated similar results as well.

Other researchers have also posited other simple models. We demonstrated the one by Hay as has been stated:

The downstream effector of PI3K, Akt, is frequently hyperactivated in human cancers. A critical downstream effector of Akt, which contributes to tumorigenesis, is mTOR. In the PI3K/Akt/mTOR pathway, Akt is flanked by two tumor suppressors: PTEN, acting as a brake upstream of Akt, and TSC1/TSC2 heterodimer, acting as a brake downstream of Akt and upstream of mTOR.

The Baldo et al model is quite similar to the Weinberg model shown initially. It clearly demonstrates the overall controlling influence of mTOR. As Baldo et al state:

There is a great body of evidence supporting consideration of the mTOR signaling system as an important network in cell regulation, differentiation and survival. mTOR is a sensor of mitogen, energy and nutritional levels, acting as a “switch” for cell-cycle progression from phase G1 to phase S.

The antibiotic Rapamycin, a potent mTOR inhibitor, has been known to the National Cancer Institute and recognized for its potential anticancer properties since the 1970s. The observation that cell lines from different cancer types exposed to low doses of Rapamycin underwent cell-cycle arrest in phase G1, provided the basis for considering mTOR as a target for cancer therapy.

Development of mTOR inhibitor compounds has proceeded empirically due to the lack of understanding of the precise molecular targets and the required dose of the new compounds . The development of Rapamycin analogs (“Rapalogs”), but also of other, structurally different, mTOR inhibitors, was directed at the selection of specific cancer type sensitivity and an optimization of pharmaceutical forms.

The mTOR pathway controls cell size and cellular proliferation.…nutrient metabolism, mRNA translation and cell survival control. Disruption of TOR leads to early embryonic death in flies and mammalian cells, indicating mTOR plays an important role in regulating cell survival. … deregulation of several mTOR components leads to modified cell proliferation patterns and, on the other, that many mTOR components are deregulated in several human cancers.

Therefore, inhibition of mTOR leads to slowing or arrest of cells in the G1 phase. Translational control may have an important role in the balance of cell survival and death, and hence for apoptosis. Importantly, components of mTOR are deregulated in some human cancers, for example, breast and colon. Alteration of PI3-K/Akt is frequently observed in head and neck cancer .

As Easton and Houghton state:

Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a number of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compounds containing minor chemical modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo.

Results from clinical trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clinical trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclinical and clinical data and recent discoveries of the function of mTOR in cancer and growth regulation.

The other observation here is that we often find multiple characterizations of the pathways. Namely there is no canonical form, and often a pathway is depicted to demonstrate a specific protein function. Thus we may see an emphasis on one set of proteins while others are neglected. As much as we currently attempt to unify this process we are left somewhat adrift in model development at this stage. This can be exemplified by now looking at the next section on LKB1. There we show its control over PTEN whereas in an earlier model we have it controlling AMPK. In reality there are multiple links as we have discussed. The literature can be even more confusing on this issue as well.

As Mendelsohn et al state:

It is now widely accepted that mTORC1 positively controls an array of cellular processes critical for growth, including protein synthesis, ribosome biogenesis, and metabolism, and negatively influences catabolic processes such as autophagy—all of which have roles in cancer pathogenesis. Elucidating the key downstream targets of mTORC1 driving these events is an intense area of research.

Originally, much of the study of mTOR relied on experiments in which rapamycin was used acutely to inhibit mTOR (which we now know was mTORC1) in cultured cells. This led to extensive characterization of the best known mTORC1 substrates eiF-4E-binding protein 1(4E-BP1) and S6 kinase 1 (S6K1), both of which regulate protein synthesis.3 In the unphosphorylated state, 4E-BP1 binds and inhibits the cap-binding protein and translational regulator eIF4E. When phosphorylated by mTOR, 4E-BP1 is relieved of its inhibitory duty, promoting eIF4E interaction with the eIF4F complex and the translation of capped nuclear transcribed mRNA.

Following co-regulatory phosphorylation by mTORC1 and another kinase called phosphatidylinositol 3-dependent kinase 1 (PDK1), S6K1 positively affects mRNA synthesis at multiple steps including initiation and elongation by phosphorylating several translational regulators. Although the preponderance of evidence indicates that S6K1 and 4E-BP1 are directly phosphorylated by mTOR, an unidentified phosphatase activity may also be involved in their regulation. For example, the rapamycin-sensitive phosphorylation site on S6K1 is rapidly dephosphorylated (i.e., within minutes) of exposure to the drug.

They continue:

Conditions that inhibit growth, such as decreased energy, low oxygen, and insufficient nutrients, are associated with the harsh microenvironment of poorly vascularized tumor. The ability of cancer cells to overcome these adverse conditions would promote tumor growth, putting the desensitization of mTORC1 signaling in the spotlight as a potential mechanism cancer cells could exploit to enhance their viability. Whether mutations in the amino acid– and glucose-sensing pathway that activates mTORC1 exist in cancer is not known. Mutations in the growth factor inputs to mTORC1 are prominent in cancer…

Therefore, understanding the contribution and relevance of mTORC1 signaling in the progression of cancers with aberrant PI3K-AKT signaling is an important area of research.

LKB1 has been demonstrated to be the underlying control element in Peutz-Jeghers syndrome, a proliferative melanocytic genetically dominant disorder. It controls certain pathways and as a result can be considered as a candidate in the development and progression of melanoma. Generally LKB1 is a gene whose protein stabilizes the growth and location of melanocytes. Understanding its impact in Peutz-Jeghers allows one to examine what happens when its function is suppressed in melanoma. Albeit not an initiator in the process, its aberration in a melanocyte argues for movement and loss of control.

In a recent paper by Liu et al the authors examine this premise and conclude that loss of LKB1 is significant especially in metastatic evolution. As Liu et al state:

Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24+ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24 cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24+ tumor subpopulation.

Earlier work by Zheng et al noted:

The LKB1-AMPK signaling pathway serves as a critical cellular sensor coupling energy homeostasis to cell growth, proliferation, and survival. However, how tumor cells suppress this signaling pathway to gain growth advantage under conditions of energy stress is largely unknown. Here, we show that AMPK activation is suppressed in melanoma cells with the B-RAF V600E mutation and that downregulation of B-RAF signaling activates AMPK. We find that in these cells LKB1 is phosphorylated by ERK and Rsk, two kinases downstream of B-RAF, and that this phosphorylation compromises the ability of LKB1 to bind and activate AMPK. Furthermore, expression of a phosphorylation-deficient mutant of LKB1 allows activation of AMPK and inhibits melanoma cell proliferation and anchorage-independent cell growth.
Thus Zheng et al putatively identified these two pathways as sources for melanoma development. Liu et al appear to have extended this to metastasis.

The LKB1 gene, also called STK11, which encodes a member of the serine/threonine kinase, regulates cell polarity and functions as a tumour suppressor. This is clearly demonstrated in the above. Now recall that mTOR is a protein kinase and is a key regulator of cell growth[6]. mTOR stimulates mRNA translation thus facilitating the conversion into proteins. mTOR also facilitates the formation of ribosomes which as an important condition of cell growth under specific physiological conditions. Through the effects of mTOR on the ribosome machinery it becomes a significant factor in increasing translational activity in a cell.

As Marks et al state regarding the above flow we have (p 337):

Activation and effects of the mTOR protein kinase By inactivating the GAP TSC2 of the small G-protein Rheb, extracellular signals stimulating the PI3K-PKB signaling cascade prompt Rheb to activate mTOR. mTOR enhances the activity of the protein kinase S6K and represses 4E-BP1 and eEF2 activities, resulting in an increased rate of translation (whether 4E-BP1 and eEF2 kinase are phosphorylated directly by mTOR, as shown here, or by S6K or by both kinases is not entirely clear).
mTOR may also be directly phosphorylated and activated by PKB.

Now Liu et al state regarding this pathway model:

Two independent pathways appear to be critically important in regulating cell growth in response to nutrient supply and mitogenic stimulation:

(i) the PKA/PRKAR1A-LKB1 tumour suppressor protein pathway, acting via AMPK, and

(ii) the PI3K/AKT pathway.

Recent evidence suggests that the tumour suppressor gene complex, TSC1/TSC2, orchestrates the signal from both pathways to the downstream target, mTOR, which in turn regulates the ribosomal protein S6 and 4EBP-1, a repressor of the translational initiation factor eIF4E. In this model, at times of nutrient stress LKB1/AMPK activation of the TSC1/TSC2 complex results in inhibition of mTOR and a decrease in protein synthesis.

Under stimulation of mitogenic pathways, PI3K phosphorylates PIP2 to PIP3 resulting in recruitment of AKT to the membrane where it is activated by PDK1. Activated AKT inhibits the TSC1/TSC2 tumour suppressor complex leading to increased mTOR activity. In the later pathway, PTEN antagonises PIP3 action through dephosphorylation, and thus provides an ‘‘off’’ switch for regulating mitogenic pathway induced cellular growth and proliferation.

Cross talk of several other pathways appears to play important regulatory roles in the lentiginoses syndromes to include the Ras/MAPK pathway in the regulation of translation, the LKB1 pathway in cellular polarity, the AKT pathway (as well as the TSC1/TSC2 complex) in the regulation of the Wnt/GSK3b/b-Cat pathway, and the BMP pathway in the regulation of PTEN (see text for further discussion). Lastly, both PTEN and mTOR appear to have negative regulatory effects on VEGF through loss of stabilisation of the hypoxia inducible transcription factor 1 (HIF1).

When LKB1 is inactivated we have the following changes observed in a melanocyte. Note the deactivation of normal LKB1 proteins as well as a PTEN loss of function. We then have the models of Bauer and Stratakis, which we graphically depicted before and they are compelling and establish a paradigm which the work of Liu et al can be considered.

Let us go back to LKB1 and its function. From NLM database we have[7]:

LKB1 is a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of other ~14 kinases, comprising AMPK and AMPK-related kinases.

Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions. Also it is known as PJS; LKB1; hLKB1.

From the results of Shaw et al we have[8]:

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive..LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. 

Also Shaw et al demonstrate several ways in which LKB1 can function when activated in vivo from either a basal or non-basal state. The description can be shown in the following Figure taken from Shaw et (Fig 6 in Shaw et al as modified):

Shaw et al describe the above as follows:

Model for LKB1 as a sensor of low energy and negative regulator of tumorigenesis and apoptosis. Under basal conditions, LKB1 serves as a sensor of low energy, keeping ATP-consuming processes including protein synthesis in check via AMPK phosphorylation of TSC2. In response to stresses such as low glucose, hypoxia, nutrient deprivation, or mitochondrial poisons, LKB1 phosphorylates AMPK, which shuts off ATP-consuming processes and up-regulates ATP production to offset the elevated AMP/ATP ratio. This activity prevents the cells from going into apoptosis in response to elevated AMP. In LKB1-deficient cells, under some basal conditions, there may be increases in TOR signaling due to the lack of TSC2 phosphorylation by AMPK, resulting in increased growth or tumorigenic potential. In response to further increases in intracellular AMP, these cells have no mechanism to offset the elevated AMP and go straight into apoptosis.

We now want to examine some of the details of each of the two medications and specifically their cellular pathway elements and how putatively the two medications may function. We begin by returning to Danzig et al and seeing what they state about the specifics.

For metformin Danzig et al remark:

Metformin has been shown to inhibit mitochondrial respiration, to induce apoptosis through activation of the AMPK/p53 pathway,

and to trigger a G2-M cell cycle arrest independent of its effect on p53.

Its AMPK activation results in diminished mTOR and S6K1 activity, impeding translation.

Independent of AMPK, metformin also induces G0/G1 cell cycle arrest via reduction of cyclin D1 levels and pRb phosphorylation.

Finally, metformin inhibits nuclear factor κB (NFkB) and Erk 1/2 and reduces levels of c-MYC.

For statins the author’s remark:

Statins, through HMG-CoA reductase inhibition, limit mevalonate production, which is used in protein prenylation.

This has been shown to induce apoptosis through Ras inhibition and to reduce invasiveness by preventing intracellular Rho relocalization.

Another cholesterol-dependent effect is statins’ interference with lipid raft signaling, which reduces activation of the PI3k/Akt proliferation pathway.

Independent of HMG-CoA reduction, statins can also induce apoptosis through the MEK/ERK pathway, inhibit cell proliferation through blockade of the G1-S and G2-M cell cycle transitions, induce apoptosis by caspase activation and reduce angiogenesis through diminished endothelial nitric oxide production.

Finally, statins inhibit leukocyte migration and the resultant inflammation, which has been linked to PCa progression.

The statin effects are significant in overall pathway modulation.

Metformin is a classic Type 2 Diabetic control medication and has been used extensively with many patients for several decades. We demonstrate below the areas in which Metformin exercises its influence.

It reduces, inhibits, and activates a variety of pathway elements all of which control cell cycles and apoptosis. It controls the metabolic cycles that relate to the pathway elements we have shown in the previous sections.

The impact of AMPK and in turn p53 is a significant pathway. AMPK is as we have seen a significant metabolic player and metformin modulates it behavior. It manages the Cyclin D1 which controls cell cycle growth. One may wonder why so effectively in the prostate, however. The mTOR management is via AMPK as well and then through mTOR C1.

As Mendelsohn et al state:

Metformin belongs to the biguanide class of antidiabetic drugs and activates the LKB1/AMPK axis (mediating glucose and energy homeostasis) and inhibits cancer cell viability through the inhibition of mTOR. Metformin can also downregulate mTOR and subsequent cell growth through AMPK-independent mechanisms. A recent study using mouse models of lung cancer to assess the protective effect of metformin suggested two possible mechanisms: decreased levels of circulating insulin and lowered energy stress leading to inhibition of mTOR.

Owing to the fact that studies show metformin is associated with a decreased risk of cancer incidence compared with other treatments (such as insulin) among diabetic patients, metformin is rightfully garnering interest for its role in cancer prevention and therapy and supports further testing in the clinical setting.

The Mendelsohn comment has been demonstrated in Danzig somewhat.

Statins are used to reduce VDL levels. The typical mechanism is shown below. The statin blocks the production of intracellular cholesterol which in turns sets off a cascade that sends out LDL receptors to collect LDL from the blood thus lowering serum LDL.

Overall this is a simple and straightforward mechanism. However, just how this affects the PCa process has been postulated in the paper we have focused on but may be likely to a topic of discussion. Chan et al have discussed several general mechanisms.

As Chan et al note:

HMG-CoA reductase inhibitors have been shown to synchronize tumor cells by blocking the transition of G1-S in the cell cycle, thereby exerting its antiproliferative effect. This effect is reversed with the addition of mevalonate. In primary cultures of human glioblastoma cells, inhibition of Ras farnesylation by lovastatin is associated with reduction of proliferation and migration. However, the inhibition of cell growth by lovastatin may be independent of Ras function .

These findings suggest that geranyl-geranylated proteins (but to a much lesser degree, farnesylated proteins such as Ras) are essential for progression of C6 glioma cells into the S phase of the cell cycle. In addition, N-Ras mutated, primary AML cells were no more sensitive to simvastatin than AML cells without the mutation, suggesting that the inhibition of AML cell proliferation by HMB-CoA reductase inhibitors may be independent of the Ras signaling pathway.

The results by Danzig et al present an interesting window to possible control of PCa expansion by using metabolic pathway elements which may also have been causative factors in its initiation. We examine here several observations which may expand the work provided therein.

Let us examine a few additional issues:

What impact will methylation have and is it also driven by similar modalities? We know that methylation is also a factor especially in inflammation like states. Thus what effect does methylation have in this specific case?

Does the process activated by metformin and statins affect all altered prostate cells including stem cells or does it deal solely with the proliferating cells? Here is the issue regarding changes not only to prostate cells but to all cells. There is no specificity of these two therapeutics to prostate cells. The affect cells across the body. Are these effects stabilizing as they may be to the prostate or are they potentially unstabilizing?

How does this combo deal with other cells? This is a corollary to the above observation. Namely here we would examine the impacts, beneficial and harmful, to other cells. These medications are modulating metabolic processes. These metabolic processes are common across many cell areas. It would be useful to see what the balanced effect is.

This must be a common combination. If so that a study may reveal a significant different in end-stage mortality in such a large population.  Namely we know that this combination is quite common. If so, then a retrospective study may be beneficial. However, as we have noted before, we do not have either compliance or detailed measurements regarding lipids or blood sugar (eg HbA1c) information.

What is the cause of the synergy between the two? As noted by Danzig et al:

Several potential mechanisms of synergism between the two medications have been explored in preclinical studies. In one study of fatty liver pathogenesis, type 2 diabetic mice fed with a high-fat diet developed increased levels of markers of inflammation and oxidative stress, including C-reactive protein, interleukin-6 and tumor necrosis factor-α. The combinatorial use of atorvastatin and metformin attenuated these effects to a significantly greater degree than either drug alone.

Another study found that the proapoptotic and anti-survival effects of an AMPK activator similar to metformin on malignant melanoma cell lines were enhanced by combination with simvastatin or fluvastatin. As discussed earlier, these two drugs are thought to have a wide range of effects on both metabolic and pleiotropic pathways.

Therefore, the possible means by which they may interact intracellularly to impact cancer behavior are plentiful and diverse.

The cause of the synergy is not really understood. Frankly, even single drug cause is at best generically understood. The range of impact of statins is not fully grasped and thus it may be the statin which has the greater effect. At this stage we need added information regarding the nature of effects.

1.               Allott, et al, Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database, BJU International, Volume 114, Issue 5, pages 661–666, November 2014
2.               Baldo, P., et al, mTOR Pathway and mTOR inhibitors as Agents for Cancer Therapy, 2008, Curr Can Drug Targets, pp 647-668.
3.               Bass, A., et al, Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD, Cell, Vol. 116, 457–466, February 6, 2004
4.               Bauer, A., C. Stratakis, The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis, J Med Genet 2005;42:801–810. doi: 10.1136
5.               Chan K, at al. The statins as anticancer agents. Clin Cancer Res 2003; 9: 10–19.\
6.               Danzig, et al, Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes, Prostate Cancer and Prostatic Disease (2015) 18, 63–68
7.               Easton, J., P. Houghton, mTOR and Cancer Therapy, Oncogene, 2006, pp 6436-6446.
8.               Kinkaide, C., et al, Targeting Akt/mTOR and ERK MAPK Signalling Inhibits Hormone Refractory Prostate Cancer in Preclinical Mouse Model, Jrl Clin Inv 2008, 99 3051-3064.
9.               Liu, A., et al, Correlated Alterations in Prostate Basal Cell Lauer and Basement Membrane, Int Jrl Bio Sci, V 5, 2009, pp 276-285.
10.            LoPiccolo, J., et al, Targeting the PI3K/Akt/mTOR Pathway, Drug Res Up, 2008, pp 32-50.
11.            Margel, D., et al, Metformin Use and All-Cause and Prostate Cancer Specific Mortality Among Men With Diabetes, JCO Sep 1, 2013:3069-3075; DOI:10.1200/JCO.2012.46.7043.
12.            Marks, F., et al, Cellular Signal Processing, Garland (New York), 2009
13.            McGarty, T. P., Obesity and Type 2 Diabetes: Cause and Effect, DOI: 10.13140/2.1.2118.5929
14.            McGarty, T. P., Prostate Cancer: A Systems Approach, DOI: 10.13140/2.1.2475.2007 
15.            Mendelsohn, et al, The Molecular Basis of Cancer, Elsevier (New York) 2014.
16.            Mihaylova, Maria,  Reuben J. Shaw, The AMPK signalling pathway coordinates cell growth, autophagy and metabolism, Nature Cell Biology13, 1016–1023 (2011) doi:10.1038/ncb2329
17.            Shackelford, D., Reuben J. Shaw, The LKB1–AMPK pathway: metabolism and growth control in tumour suppression, Nature Reviews Cancer 9, 563-575 (August 2009) | doi:10.1038/nrc2676
18.            Shao, et al, Inhibition of Polo-like Kinase 1 (Plk1) Enhances the Antineoplastic Activity of Metformin in Prostate Cancer, J. Biol. Chem. 2015 290: 2024-2033.
19.            Shaw, R., The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress, PNAS March 9, 2004  vol. 101 no. 10 3329–3335
20.            Weinberg, R., Cancer, Garland (New York), 2008.
21.            Weinberg, R., The Biology of Cancer, Garland (New York) 2007.
22.            Zheng, L. et al, NF-kB Regulates Androgen Receptor Expression and Prostate Cancer Growth, Am Soc Invest Path, V 175, 2009, pp 489-499.