Using Off-Label Drugs for Cancer Prevention and Adjuvant Treatment.
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.
Aspirin: An Old Friend with a New Indication
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[R] 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.
Cimetidine: More than Just Heartburn Relief
The drug cimetidine (brand name Tagamet[R]) 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 Off-Label Drugs for Cancer Prevention * 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.
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 anticancer 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.
Valproic Acid: Multiple Mechanisms of Action
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 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.
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.
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[R] Wellness Specialist at 1-866-864-3027.
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TABLE 1: ASPIRIN EFFECTS ON RISK OF DEVELOPING CANCERS Cancer Type Aspirin-Associated Reduction in Risk * of Developing Cancer Breast (67) 10% Lung (68) 13%-26% Ovary (69) 15% Uterine lining (endometrium) (70) 7% Stomach (71) 30% Colorectal (Risk of 20%-25% Recurrence of Polyps) (72,73) * Compared with non-use of aspirin TABLE 2: STATIN EFFECTS ON CANCER SURVIVAL BY TYPE OF MALIGNANCY Cancer Type Statin-Associated Risk Reduction * for: Dying from Dying from Having a Any Cause Cancer Recurrence of Cancer Breast (23) NR ** 30% 36% Prostate (62) 44% 47% NR ** Prostate (63) NR ** 32% 12% Pancreatic (64) NR ** 25% NR ** Kidney (22) 26% 33% NR ** Statin-Associated Reduction in Risk of Developing Cancer Liver (65) 40% Liver (66) 56% (Asian); 51% (Caucasian) * Compared with non-use of statins; ** NR = Not Reported in Study TABLE 3: METFORMIN EFFECTS ON CANCER RISK AND SURVIVAL Cancer Type Metformin-Associated Risk Reduction * for: Dying from Cancer Developing Any Cause Progression Cancer or Pre-Malignant Lesion Lung (74) 23% 47% Pancreas (75) 22% NR ** Pancreas (76) 23% NR ** Endometrium 42% 39% (Uterine lining) (77) Endometrium (78) 18% NR ** Endometrium (79) 36%-50% NR ** Endometrium (80) 49% 37% Colorectal (81) 18% NR ** Stomach (82) 24% Colorectal Polyp 24% (pre-malignant lesion) (83) Liver Cancer in 48% Diabetics (84) * Compared with non-use of metformin; ** NR = Not Reported in Study
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|Date:||Oct 1, 2018|
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