Life Extension Magazine®

Issue: Oct 2018

Using Off-Label Drugs for Cancer Prevention and Adjuvant Treatment

Cancer cells adapt to toxic environments (such as chemotherapy) and rapidly mutate to escape eradication. Prudent use of adjuvant “off-label” drugs can improve odds of a complete response.

By Kathy Parker

This year, more than 600,000 Americans will perish from cancer.1

Millions endure harsh treatments that are often only partially effective.

Many of these human tragedies are avoidable.

Overlooked by oncologists are commonly used drugs that have demonstrated activity against cancer.

These include over-the-counter medications like aspirin and cimetidine, and prescription drugs like statins and metformin.

In addition to combatting factors that initiate cancer, studies show that some of these drugs can help reduce the risk of dying from cancer.

In this article, we’ll review how six drugs that are approved by the FDA for other indications can be used “off-label” as adjuvant (meaning “in addition to”) therapies to help prevent, eradicate, or slow the progression of different types of cancer.

What you need to know

  • Despite scientific progress, we still have a long way to go in the war on cancer.
  • As scientific knowledge grows about what causes cancer to develop to begin with, we are finding that numerous drugs that were developed for other indications ultimately have important anti-cancer effects.
  • Drugs such as statin medications, aspirin, valproic acid, metformin, beta-blockers, and cimetidine all have mechanisms of action that impact the basic processes that promote cancer development, invasion, and metastases.
  • Most of these drugs have multitargeted effects that enable them to block pro-malignancy processes at multiple checkpoints.
  • As a result, numerous studies have shown that many of these drugs can reduce the risk of developing—or dying from—cancer.

Aspirin: An Old Friend with a New Indication

Aspirin  

Aspirin was originally derived from willow bark and has been used to ease fevers and inflammation for 3,500 years.2-4

Aspirin has an ability to inhibit enzymes that make pro-inflammatory signaling factors.5 This enables aspirin to reduce platelet activation which makes it useful for preventing blood clots that form in coronary arteries and cause heart attacks.

These same mechanisms also have a role in aspirin’s anti-cancer effects.

Once cancer has formed, activated platelets contribute to its spread (metastasis) while inflammation fuels tumor growth.6,7 Aspirin’s ability to combat these actions makes it effective in reducing cancer incidence and death.7

The benefits of aspirin have become so apparent that the U.S. Preventive Services Task Force now recommends using aspirin to prevent colorectal cancer and cardiovascular disease in certain groups of people.8,9

A pooled analysis of two large population-level studies provides validation of this recommendation.

In a long-term study of over 100,000 people, regular aspirin use was associated with a significant overall reduced risk for developing cancer. This reduction was primarily due to its ability to reduce the risk of intestinal cancers—especially colorectal cancers.8

The benefits of aspirin in this study were evident even at doses of 162 mg to 490 mg of aspirin per week. People had to be taking aspirin for at least six years to show this cancer-preventive benefit.8

A number of other studies document the potential of low-dose aspirin to protect against many other malignancies, including pancreatic, breast, lung, ovarian, esophageal and stomach (see Table 1).

Cancer patients should consider taking an enteric coated aspirin, with a dose range of 81 mg to 325 mg per day.

Life Extension® has provided data about using aspirin as an adjuvant cancer treatment for decades. Yet most patients and their doctors overlook aspirin because it sounds too simplistic.

The underlying data, however, reveals probable efficacy. Since there is no money to be made promoting aspirin as an adjuvant cancer therapy, it is unlikely to achieve the recognition it deserves.

Table 1: Aspirin Effects on Risk of Developing Cancers

Cancer Type

Aspirin-Associated Reduction in Risk* of Developing Cancer

Breast67

10%

Lung68

13%-26%

Ovary69

15%

Uterine lining (endometrium)70

7%

Stomach71

30%

Colorectal (Risk of Recurrence of Polyps)72,73

20%-25%

*Compared with non-use of aspirin

Cimetidine: More than Just Heartburn Relief

The drug cimetidine (brand name Tagamet®) was among the first pills designed to relieve heartburn. It works by blocking histamine receptors in the stomach lining that promote acid secretion.

Cimetidine has demonstrated multiple anti-cancer effects.

For example, it can reduce levels of adhesion molecules that help cancer cells stick to cells lining the inside of blood vessels—an action that can prevent local invasion and metastasis.10-13

Cimetidine has also been shown to:10,11,14-18

  • Mobilize natural killer cell activity and other immune factors that attack cancer cells.
  • Block an increase in T-suppressor cells that prematurely turns off certain immune functions.
  • Reduce activity of signaling pathways that stimulate new blood-vessel formation (angiogenesis), a requirement for tumors to nourish themselves during rapid growth.

Back in 1985, Life Extension first recommended cimetidine as an adjuvant cancer treatment. Since then, many scientific papers have documented the remarkable survival improvements in cancer patients using this drug.19

In one study, gastric cancer patients received either cimetidine (800 mg per day) or placebo immediately after surgery or the decision not to operate. Median survival in the cimetidine group was 450 days compared to 316 days in the placebo group.20

A meta-analysis found that taking cimetidine resulted in a 47% improvement in overall survival in colorectal cancer patients who underwent curative surgery, compared with those who did not.12

Studies indicate the importance of cancer patients to initiate cimetidine five days before surgery and to continue taking 800 mg a day for one year after surgery (in addition to standard therapies).

What You Need to Know

Statin Drugs: Evidence in Human Trials

Statin drugs were developed to lower blood cholesterol levels. These drugs block an enzyme that the liver uses to make cholesterol, which results in less cholesterol production and hence lower blood cholesterol levels.21-23 Many people avoid long-term statin use because of side effects.

When it comes to cancer, however, the side effects of statins may be tolerable if there is clinical indication that anti-cancer effects are manifesting.

Some tumor cells require copious activity of the same enzyme pathways involved in producing cholesterol. Statins block the production of those biochemical building blocks.21 This ability makes statins potentially appealing for cancer prevention if one also requires them to lower elevated LDL cholesterol.

Statins can also function as AMPK activators, which contributes to their anti-cancer effects.

Intriguing results have been reported for a variety of cancer types, including breast, prostate, pancreas, kidney, and liver (see Table 2 on the next page).

It’s important to note that not all statins are alike in their anti-cancer benefits. Those that dissolve better in fats (called lipophilic statins) consistently show better results than those that dissolve best in water (hydrophilic statins).23-25 Atorvastatin, lovastatin, and simvastatin are lipophilic, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic.26

We at Life Extension are well aware of the challenges and concerns with statin drug use. We’ve published articles in the past advocating for lower dose and every-other-day statin use for those with elevated LDL who cannot reduce it with diet and lifestyle changes.27-30

Still, we can’t ignore published findings indicating potential adjuvant cancer treatment benefits.

For those battling cancer, a lipophilic statin should be considered, such as atorvastatin with a dose range of 20 mg to 80 mg per day. The higher doses may only be tolerable for a few weeks and dosage reduction can be considered if tumor markers and imaging results indicate clinical improvements. There are not yet specific guidelines available in the published literature to indicate how long a cancer patient should consider using statins as adjuvant treatment.

 

Table 2: Statin Effects on Cancer Survival by Type of Malignancy

Cancer Type

Statin-Associated Risk Reduction* for:

Dying from Any Cause Dying from Cancer Having a Recurrence of Cancer
Breast23 NR** 30% 36%
Prostate62 44% 47% NR**
Prostate63 NR** 32% 12%
Pancreatic64 NR** 25% NR**
Kidney22 26% 33% NR**
 

Statin-Associated Reduction in Risk of Developing Cancer

Liver65 40%
Liver66 56% (Asian); 51% (Caucasian)

*Compared with non-use of statins; **NR = Not Reported in Study

Valproic Acid: Multiple Mechanisms of Action

Valproic Acid  

Valproic acid is derived from valeric acid, a compound naturally found in the valerian plant (Valeriana officinalis).31

Valproic acid’s primary medical use is to treat and prevent epileptic seizures, though new properties are coming to light.

One of the most exciting of these findings is valproic acid’s impact on cancer cells. It has been shown to have at least four different mechanisms of action against cancer:

• It can inhibit enzymes that selectively “close” segments of chromosomes for transcription of genes.32 In cancer, this remarkable property can promote the transformation of “generic” cells into healthy cells rather than cancerous ones.32-34 Thus, valproic acid has the ability to help determine a cell’s fate.

• Valproic acid acts on signaling pathways that decrease the growth and spread of tumors in animal models. This is due in part to its ability to stop the cell cycle, which essentially “freezes” cancer cells in the midst of uncontrolled proliferation.35-37

• Valproic acid induces natural, programmed cell death, or apoptosis. Cancer cells lose the ability to succumb to apoptosis. This allows them to reproduce without limit, essentially making them “immortal.”32,36,38-41

• Valproic acid can make malignant cells more “visible” to the immune system’s natural killer cells, helping them identify and destroy emerging tumors.33

Animal and cell culture studies have now shown that valproic acid exerts one or more of these anti-cancer effects in numerous types of tumors, including ovarian, cervical, salivary gland, pancreas, thyroid, and head-and-neck cancers.33,35,37-40 It has also been found to have synergistic effects with aspirin in damaging liver cancer cells in culture.41

A meta-analysis showed that patients with the brain tumor glioblastoma multiforme may live longer when treated with valproic acid.42

And several other early safety and dosing studies have established that valproic acid is safe and well tolerated.42-44

Cancer (especially glioblastoma) patients should consider valproic acid at a dose of 25 mg per kilogram of body weight per day.

Metformin: Multitargeted Biotherapy

Metformin  

Metformin is a drug with true multitargeted properties. Originally derived from the French lilac plant (Galega officinalis), metformin has been the gold standard for treating type II diabetes for several decades and has accumulated an impressive record of safety and effectiveness.45-48

Over time, evidence began to emerge showing that diabetic patients treated with metformin had lower incidence—and higher survival rates—of several cancers, compared to those not treated with metformin.48-50

Indeed, one 2017 study showed that diabetics taking metformin had a 7% reduction in all-cause death rates compared with nondiabetics.51 This is an interesting finding given that diabetics typically die sooner than nondiabetics. Also of note, the diabetics taking metformin were 28% less likely to die than diabetics taking other therapies.51

Metformin can alter how cells manage energy and how they read out genetic information. Both are crucial factors in the progression from a single malignant cell into a deadly tumor.

By one mechanism, metformin activates the AMPK complex, a master metabolic regulator that controls how and when food energy is either used or stored. “Switching on” AMPK leads to a cascade of events that slow or stop cell proliferation in cancer.48,50,52

Via a second mechanism, metformin shuts down genes in tumor-promoting pathways, further helping to inhibit cell proliferation.52

Metformin also reduces blood glucose and insulin levels. Cancer cells use glucose and insulin to fuel their rapid proliferation.

Metformin reduces the risk of pancreatic cancer through antidiabetic and antitumor actions.53 Research shows that metformin users (including diabetics) have a significantly lower risk for developing pancreatic cancer.54

In a controlled study at MD Anderson Cancer Center, the risk of pancreatic cancer was 62% lower in diabetics who had taken metformin compared to those who had never taken it.55

Human studies provide strong evidence for metformin’s important role in cancer prevention and mitigation, as shown in Table 3.

Cancer patients should consider metformin at a dose of 1,000 mg, two times a day with meals.

Table 3: Metformin Effects on Cancer Risk and Survival

Cancer Type

Metformin-Associated Risk Reduction* for:

Dying from Any Cause Cancer Progression Developing Cancer or
Pre-Malignant Lesion
Lung74 23% 47%  
Pancreas75 22% NR**
Pancreas76 23% NR**
Endometrium
(Uterine lining)77
42% 39%
Endometrium78 18% NR**
Endometrium79 36%-50% NR**
Endometrium80 49% 37%
Colorectal81 18% NR**
Stomach82   24%
Colorectal Polyp
(pre-malignant lesion)83
24%
Liver Cancer in Diabetics84 48%

*Compared with non-use of metformin; **NR = Not Reported in Study

Beta-Blockers: Fight Cancer by Blunting Stress Effects

Beta-Blockers Fight Cancer by Blunting Stress Effects  

Our bodies respond to stress with an immediate burst of the “fight-or-flight” neurotransmitters epinephrine (adrenaline) and norepinephrine. This has the beneficial effect of ramping up heart rate, blood pressure, and overall vigilance to better enable us to cope with a threat.

But chronic stress causes the continuous outpouring of these potent neurotransmitters—even when there is no obvious threat. This can promote the growth and spread of tumors by activating their cell-surface receptors, which causes cells to lose their regulation over replication.56

Drugs called beta-blockers reduce the harmful impact of epinephrine and norepinephrine on heart rate and blood pressure. But because these drugs act by blocking the adrenaline receptors, they are also likely to reduce the impact these neurotransmitters have on cancer progression.

Human studies show intriguing potential.

In an observational study of 1,340 diabetics, those taking beta-blockers had a 67% lower overall risk of cancer compared with those not taking the drugs. Further analysis showed a 13% reduction in cancer risk for each month of exposure to beta-blockers.57

The specific cancers with the most compelling research in this area are breast and prostate cancer.

One meta-analysis found that using beta-blockers produced a 50% reduction in the risk of dying from breast cancer, compared with non-users.56

Another showed that women who were already using beta-blockers when they were diagnosed had a 56% improvement in their overall chance of surviving breast cancer.58

With regards to prostate cancer, a meta-analysis showed that using beta-blockers was associated with a 15% reduction in the risk of dying from the cancer, compared with non-use.59

Please note that choosing a specific dose for beta-blockers is challenging given that most of the studies look at retrospective population groups and specific doses used are not noted. For that reason, a wide range of doses has been used without a specific dose for cancer treatment being identified.

The two beta-blocker drugs that demonstrate anti-cancer potential are propranolol and carvedilol.

For propranolol, the Physician’s Desk Reference lists 80 mg to 480 mg for the treatment of hypertension, and 180 mg to 240 mg for the reduction of cardiovascular mortality in stable patients with a history of heart attack caused by coronary occlusion.

With regard to carvedilol, Physician’s Desk Reference listed 12.5 mg to 50 mg for the treatment of hypertension.

Due to the side effect profile of beta-blockers, work closely with your prescribing physician when considering which one to choose and the appropriate starting dose.

Dosing in the lower ranges of either propranolol or carvedilol may be considered by cancer patients in coordination with their oncologist.

At the time of this writing, there are direct intervention trials seeking to verify whether certain beta-blockers can effectively reduce cancer risks.60,61 When results of these studies are published, a clearer picture will emerge as to whether these drugs should be considered by healthy individuals. In addition to potential cancer risk reduction, beta-blockers can beneficially lower blood pressure in certain individuals.

Summary

cancer treatment  

Most cancer treatments still involve some form of chemotherapy, with or without radiation treatment, immune modulation, and/or surgery.

But as the search for a cure continues, new tools are appearing—many of them in the form of drugs that have long been in use for entirely different indications.

A review of the recent literature shows that six widely used prescription and over-the-counter drugs may have considerable efficacy against cancer. Some have mechanisms of action that reduce the size and spread of tumors, while others have been found to improve survival rates in people with cancer.

These drugs act by multiple mechanisms, which give them an edge in fighting cancer. That’s because cancer cells have the ability to rapidly evolve in order to escape eradication by conventional and alternative treatments.

Anyone interested in reducing their cancer risk should talk to their doctor about taking advantage of drugs that are supported by peer-reviewed published studies, yet overlooked by most of the oncology establishment.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Available at: https://www.cancer.gov/about-cancer/understanding/statistics. Accessed July 30, 2018.
  2. Desborough MJR, Keeling DM. The aspirin story - from willow to wonder drug. Br J Haematol. 2017;177(5):674-83.
  3. Shara M, Stohs SJ. Efficacy and Safety of White Willow Bark (Salix alba) Extracts. Phytother Res. 2015;29(8):1112-6.
  4. Wood JN. From plant extract to molecular panacea: a commentary on Stone (1763) ‘An account of the success of the bark of the willow in the cure of the agues’. Philos Trans R Soc Lond B Biol Sci. 2015;370(1666).
  5. Ma J, Cai Z, Wei H, et al. The anti-tumor effect of aspirin: What we know and what we expect. Biomed Pharmacother. 2017;95:656-61.
  6. Takiuchi T, Blake EA, Matsuo K, et al. Aspirin use and endometrial cancer risk and survival. Gynecol Oncol. 2018;148(1):222-32.
  7. Di Francesco L, Lopez Contreras LA, Sacco A, et al. New Insights into the Mechanism of Action of Aspirin in the Prevention of Colorectal Neoplasia. Curr Pharm Des. 2015;21(35):5116-26.
  8. Cao Y, Nishihara R, Wu K, et al. Population-wide Impact of Long-term Use of Aspirin and the Risk for Cancer. JAMA Oncol. 2016;2(6):762-9.
  9. Available at: https://www.uspreventiveservicestaskforce.org/page/document/recommendationstatementfinal/aspirin-to-prevent-cardiovascular-disease-and-cancer. Accessed July 24, 2018.
  10. Losurdo G, Principi M, Girardi B, et al. Histamine and Histaminergic Receptors in Colorectal Cancer: From Basic Science to Evidence-based Medicine. Anticancer Agents Med Chem. 2018;18(1):15-20.
  11. Borentain P, Carmona S, Mathieu S, et al. Inhibition of E-selectin expression on the surface of endothelial cells inhibits hepatocellular carcinoma growth by preventing tumor angiogenesis. Cancer Chemother Pharmacol. 2016;77(4):847-56.
  12. Deva S, Jameson M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. Cochrane Database Syst Rev. 2012;8:Cd007814.
  13. Kobayashi K, Matsumoto S, Morishima T, et al. Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 2000;60(14):3978-84.
  14. Adams WJ, Morris DL, Ross WB, et al. Cimetidine preserves non-specific immune function after colonic resection for cancer. Aust N Z J Surg. 1994;64(12):847-52.
  15. Hansbrough JF, Zapata-Sirvent RL, Bender EM. Prevention of alterations in postoperative lymphocyte subpopulations by cimetidine and ibuprofen. Am J Surg. 1986;151(2):249-55.
  16. Adams WJ, Lawson JA, Nicholson SE, et al. The growth of carcinogen-induced colon cancer in rats is inhibited by cimetidine. Eur J Surg Oncol. 1993;19(4):332-5.
  17. Kubecova M, Kolostova K, Pinterova D, et al. Cimetidine: an anticancer drug? Eur J Pharm Sci. 2011;42(5):439-44.
  18. Siegers CP, Andresen S, Keogh JP. Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date. Digestion. 1999;60(5):415-21.
  19. Pantziarka P, Bouche G, Meheus L, et al. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience. 2014;8:485.
  20. Tonnesen H, Knigge U, Bulow S, et al. Effect of cimetidine on survival after gastric cancer. Lancet. 1988;2(8618):990-2.
  21. Iannelli F, Lombardi R, Milone MR, et al. Targeting Mevalonate Pathway in Cancer Treatment: Repurposing of Statins. Recent Pat Anticancer Drug Discov. 2018;13(2):184-200.
  22. Nayan M, Punjani N, Juurlink DN, et al. Statin use and kidney cancer survival outcomes: A systematic review and meta-analysis. Cancer Treat Rev. 2017;52:105-16.
  23. Manthravadi S, Shrestha A, Madhusudhana S. Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta-analysis. Int J Cancer. 2016;139(6):1281-8.
  24. Campbell MJ, Esserman LJ, Zhou Y, et al. Breast cancer growth prevention by statins. Cancer Res. 2006;66(17):8707-14.
  25. Liu B, Yi Z, Guan X, et al. The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis. Breast Cancer Res Treat. 2017;164(1):1-11.
  26. Available at: https://www.medscape.com/viewarticle/561128. Accessed July 18, 2018.
  27. Available at: https://www.lifeextension.com/magazine/2003/3/awsi/page-01. Accessed July 30, 2018.
  28. Available at: https://www.lifeextension.com/magazine/2003/3/cover_effects/page-01. Accessed July 30, 2018.
  29. Available at: https://www.lifeextension.com/magazine/2007/8/report_lipitor. Accessed July 30, 2018.
  30. Available at: https://www.lifeextension.com/magazine/2008/5/consumers-misled-about-cholesterol-and-statin-drugs/page-01. Accessed July 30, 2018.
  31. Eadie MJ. Could valerian have been the first anticonvulsant? Epilepsia. 2004;45(11):1338-43.
  32. Cincarova L, Zdrahal Z, Fajkus J. New perspectives of valproic acid in clinical practice. Expert Opin Investig Drugs. 2013;22(12):1535-47.
  33. Shi P, Yin T, Zhou F, et al. Valproic acid sensitizes pancreatic cancer cells to natural killer cell-mediated lysis by upregulating MICA and MICB via the PI3K/Akt signaling pathway. BMC Cancer. 2014;14:370.
  34. Wittenburg LA, Gustafson DL, Thamm DH. Phase I pharmacokinetic and pharmacodynamic evaluation of combined valproic acid/doxorubicin treatment in dogs with spontaneous cancer. Clin Cancer Res. 2010;16(19):4832-42.
  35. Nagai H, Fujioka-Kobayashi M, Ohe G, et al. Antitumour effect of valproic acid against salivary gland cancer in vitro and in vivo. Oncol Rep. 2014;31(3):1453-8.
  36. Sidana A, Wang M, Shabbeer S, et al. Mechanism of growth inhibition of prostate cancer xenografts by valproic acid. J Biomed Biotechnol. 2012;2012:180363.
  37. Tsai C, Leslie JS, Franko-Tobin LG, et al. Valproic acid suppresses cervical cancer tumor progression possibly via activating Notch1 signaling and enhances receptor-targeted cancer chemotherapeutic via activating somatostatin receptor type II. Arch Gynecol Obstet. 2013;288(2):393-400.
  38. Hardin H, Yu XM, Harrison AD, et al. Generation of Novel Thyroid Cancer Stem-Like Cell Clones: Effects of Resveratrol and Valproic Acid. Am J Pathol. 2016;186(6):1662-73.
  39. Shan Z, Feng-Nian R, Jie G, et al. Effects of valproic acid on proliferation, apoptosis, angiogenesis and metastasis of ovarian cancer in vitro and in vivo. Asian Pac J Cancer Prev. 2012;13(8):3977-82.
  40. Lee SH, Nam HJ, Kang HJ, et al. Valproic acid suppresses the self-renewal and proliferation of head and neck cancer stem cells. Oncol Rep. 2015;34(4):2065-71.
  41. Li X, Zhu Y, He H, et al. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells. Biochem Biophys Res Commun. 2013;436(2):259-64.
  42. Yuan Y, Xiang W, Qing M, et al. Survival analysis for valproic acid use in adult glioblastoma multiforme: a meta-analysis of individual patient data and a systematic review. Seizure. 2014;23(10):830-5.
  43. Espinoza-Zamora JR, Labardini-Mendez J, Sosa-Espinoza A, et al. Efficacy of hydralazine and valproate in cutaneous T-cell lymphoma, a phase II study. Expert Opin Investig Drugs. 2017;26(4):481-7.
  44. Iwahashi S, Utsunomiya T, Imura S, et al. Effects of valproic acid in combination with S-1 on advanced pancreatobiliary tract cancers: clinical study phases I/II. Anticancer Res. 2014;34(9):5187-91.
  45. Perla V, Jayanty SS. Biguanide related compounds in traditional antidiabetic functional foods. Food Chem. 2013;138(2-3):1574-80.
  46. Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes. 2017;18(1):10-6.
  47. Wrobel MP, Marek B, Kajdaniuk D, et al. Metformin - a new old drug. Endokrynol Pol. 2017;68(4):482-96.
  48. Crawley D, Chandra A, Loda M, et al. Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer. BMC Cancer. 2017;17(1):494.
  49. Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2(6):57.
  50. Grossmann ME, Yang DQ, Guo Z, et al. Metformin Treatment for the Prevention and/or Treatment of Breast/Mammary Tumorigenesis. Curr Pharmacol Rep. 2015;1(5):312-23.
  51. Campbell JM, Bellman SM, Stephenson MD, et al. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev. 2017;40:31-44.
  52. Zhong T, Men Y, Lu L, et al. Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene. 2017;36(17):2345-54.
  53. Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg? Pancreas. 2011;40(3):339-51.
  54. Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20.
  55. Li D, Yeung SC, Hassan MM, et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482-8.
  56. Childers WK, Hollenbeak CS, Cheriyath P. beta-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis. Clin Breast Cancer. 2015;15(6):426-31.
  57. Monami M, Filippi L, Ungar A, et al. Further data on beta-blockers and cancer risk: observational study and meta-analysis of randomized clinical trials. Curr Med Res Opin. 2013;29(4):369-78.
  58. Raimondi S, Botteri E, Munzone E, et al. Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis. Int J Cancer. 2016;139(1):212-9.
  59. Lu H, Liu X, Guo F, et al. Impact of beta-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets Ther. 2015;8:985-90.
  60. Available at: https://clinicaltrials.gov/ct2/show/nct02013492. Accessed July 30, 2018.
  61. Available at: https://clinicaltrials.gov/ct2/show/nct01847001. Accessed July 30, 2018.
  62. Meng Y, Liao YB, Xu P, et al. Statin use and mortality of patients with prostate cancer: a meta-analysis. Onco Targets Ther. 2016;9:1689-96.
  63. Tan P, Wei S, Yang L, et al. The effect of statins on prostate cancer recurrence and mortality after definitive therapy: a systematic review and meta-analysis. Sci Rep. 2016;6:29106.
  64. Jian-Yu E, Graber JM, Lu SE, et al. Effect of Metformin and Statin Use on Survival in Pancreatic Cancer Patients: a Systematic Literature Review and Meta-analysis. Curr Med Chem. 2018;25(22):2595-607.
  65. Zhong GC, Liu Y, Ye YY, et al. Meta-analysis of studies using statins as a reducer for primary liver cancer risk. Sci Rep. 2016;6:26256.
  66. Yi C, Song Z, Wan M, et al. Statins intake and risk of liver cancer: A dose-response meta analysis of prospective cohort studies. Medicine (Baltimore). 2017;96(27):e7435.
  67. Zhong S, Chen L, Zhang X, et al. Aspirin use and risk of breast cancer: systematic review and meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev. 2015;24(11):1645-55.
  68. Hochmuth F, Jochem M, Schlattmann P. Meta-analysis of aspirin use and risk of lung cancer shows notable results. Eur J Cancer Prev. 2016;25(4):259-68.
  69. Zhang D, Bai B, Xi Y, et al. Is aspirin use associated with a decreased risk of ovarian cancer? A systematic review and meta-analysis of observational studies with dose-response analysis. Gynecol Oncol. 2016;142(2):368-77.
  70. Zhang D, Bai B, Xi Y, et al. Can Aspirin Reduce the Risk of Endometrial Cancer?: A Systematic Review and Meta-analysis of Observational Studies. Int J Gynecol Cancer. 2016;26(6):1111-20.
  71. Huang XZ, Chen Y, Wu J, et al. Aspirin and non-steroidal anti-inflammatory drugs use reduce gastric cancer risk: A dose-response meta-analysis. Oncotarget. 2017;8(3):4781-95.
  72. Veettil SK, Lim KG, Ching SM, et al. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMC Cancer. 2017;17(1):763.
  73. Veettil SK, Teerawattanapong N, Ching SM, et al. Effects of chemopreventive agents on the incidence of recurrent colorectal adenomas: a systematic review with network meta-analysis of randomized controlled trials. Onco Targets Ther. 2017;10:2689-700.
  74. Cao X, Wen ZS, Wang XD, et al. The Clinical Effect of Metformin on the Survival of Lung Cancer Patients with Diabetes: A Comprehensive Systematic Review and Meta-analysis of Retrospective Studies. J Cancer. 2017;8(13):2532-41.
  75. Dong YW, Shi YQ, He LW, et al. Effects of metformin on survival outcomes of pancreatic cancer: a meta-analysis. Oncotarget. 2017;8(33):55478-88.
  76. Zhou DC, Gong H, Tan CQ, et al. Prognostic significance of anti-diabetic medications in pancreatic cancer: A meta-analysis. Oncotarget. 2017;8(37):62349-57.
  77. Guo J, Xu K, An M, et al. Metformin and endometrial cancer survival: a quantitative synthesis of observational studies. Oncotarget. 2017;8(39):66169-77.
  78. Meireles CG, Pereira SA, Valadares LP, et al. Effects of metformin on endometrial cancer: Systematic review and meta-analysis. Gynecol Oncol. 2017;147(1):167-80.
  79. Perez-Lopez FR, Pasupuleti V, Gianuzzi X, et al. Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus. Maturitas. 2017;101:6-11.
  80. Xie W, Li T, Yang J, et al. Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis. Oncotarget. 2017;8(42):73079-86.
  81. Tian S, Lei HB, Liu YL, et al. The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta-analysis. Chronic Dis Transl Med. 2017;3(3):169-75.
  82. Zhou XL, Xue WH, Ding XF, et al. Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies. Oncotarget. 2017;8(33):55622-31.
  83. Jung YS, Park CH, Eun CS, et al. Metformin use and the risk of colorectal adenoma: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2017;32(5):957-65.
  84. Ma S, Zheng Y, Xiao Y, et al. Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients. Medicine (Baltimore). 2017;96(19):e6888.

Subscribe to Life Extension Magazine®

Subscribe Now

Advertise in Life Extension Magazine®

Learn More