Cancer Treatment: The Critical Factors
Step Five: Suppressing Ras Oncogene Expression
The family of proteins known as Ras plays a central role in the regulation of cell growth. It fulfills this fundamental role by integrating the regulatory signals that govern the cell cycle and proliferation.
Defects in the Ras-Raf pathway can result in cancerous growth. Mutant Ras genes were among the first oncogenes identified for their ability to transform cells into a cancerous phenotype (ie, a cell observably altered because of distorted gene expression). Mutations in one of three genes (H, N, or K-Ras) encoding Ras proteins are associated with upregulated cell proliferation and are found in an estimated 30‒40% of all human cancers. The highest incidences of Ras mutations are found in cancers of the pancreas (80%), colon (50%), thyroid (50%), lung (40%), liver (30%), melanoma (30%), and myeloid leukemia (30%).57-63
The differences between oncogenes and normal genes can be slight. The mutant protein that an oncogene ultimately creates may differ from the healthy version by only a single amino acid, but this subtle variation can radically alter the protein's functionality.
The Ras-Raf pathway is used by human cells to transmit signals from the cell surface to the nucleus. Such signals direct cells to divide, differentiate, or even undergo programmed cell death (apoptosis).
A Ras gene usually behaves as a relay switch within the signal pathway that instructs the cell to divide. In response to stimuli transmitted to the cell from outside, cell-signaling pathways are activated. In the absence of stimulus, the Ras protein remains in the "off" position. A mutated Rasprotein gene behaves like a switch stuck on the "on" position, continuously misinforming the cell, instructing it to divide when the cycle should be turned off.64,65 Researchers have known for some time that injecting anti-Ras antibodies, specific for amino acid 12, cause a reversal of excessive proliferation and a transient alteration of the mutated cell to one of a normal appearance.66 Recently, scientists have taken advantage of the high frequency at which K-Ras is mutated in several types of cancer by developing vaccines that trigger the immune system to attack cells harboring this mutant protein. For example, a 2011 study found that patients with resected pancreatic cancer were much more likely to be alive 10 years post vaccination (20%) than those who did not receive the vaccine (0%).67
To establish new methods for diagnosing pancreatic cancer, K-Ras mutations were examined in the pancreatic juice of pancreatic cancer patients. Pancreatic juice was positive for K-Ras in 87.8% (36/41) of patients.68 When combined with p53 mutations in the stool and CA 19-9 (a blood marker for pancreatic cancer), it may be possible to identify the disease much earlier than by conventional diagnostic methods.69
Greater understanding regarding the activity of mutant Ras genes opens exciting avenues of treatment. Researchers found that precursor Ras genes must undergo several biochemical modifications to become mature, active versions. After such maturation, the Ras proteins attach to the inner surface of the cells outer membrane where they can interact with other cellular proteins and stimulate cell growth.
The events resulting in mature Ras genes take place in three steps, the most critical being the first—referred to as the farnesylation step. A specific enzyme, farnesyl-protein transferase (FPTase), speeds up the reaction. One strategy for blocking Ras protein activity has been to inhibit FPTase. Inhibitors of this enzyme block the maturation of Ras protein and reverse the cancerous transformation induced by mutant Ras genes.65
A number of natural substances impact the activity of Ras oncogenes. For example, limonene is a substance found in the essential oils of citrus products. Limonene has been shown to act as a farnesyl transferase inhibitor. Administering high doses of limonene to cancer-bearing animals blocks the farnesylation of Ras, thus inhibiting cell replication.70,71 Curcumin inhibited the farnesylation of RAS, and caused cell death in breast cancer cells expressing RAS mutations.72,73
Japanese researchers examined the effects of vitamin E on the presence of K-Ras mutations in mice with lung cancer. Prior to treatment with vitamin E, K-Ras mutations were present in 64% of the mice. After treatment with vitamin E, only 18% of the mice expressed K-Ras mutations.74 Vitamin E decreased levels of H-Ras proteins in cultured melanoma cells.75 A study conducted at Mercy Hospital of Pittsburgh also showed that diallyl disulfide, a naturally occurring organosulfide from garlic, inhibits p21 H-Ras oncogenes, displaying a significant restraining effect on tumor growth.76
Researchers at Rutgers University investigated the ability of different green and black tea polyphenols to inhibit H-Ras oncogenes. The Rutgers team found that all the major polyphenols contained in green and black tea except epicatechin showed strong inhibition of cell growth.77 Investigators at Texas A&M University also found that fish oil decreased colonic Ras membrane localization and reduced tumor formation in rats. In view of the central role of oncogenic Ras in the development of colon cancer, the finding that omega-3 fatty acids modulate Ras activation could explain why dietary fish oil protects against colon cancer.78
Statins are a class of popular cholesterol-lowering drugs. Mevacor (lovastatin), Zocor (simvastatin), and Pravachol (pravastatin) are statin drugs shown to inhibit the activity of Ras oncogenes.79 Statin drugs block the HMG-COA) reductase enzyme, which depletes cells of farnesyl pyrophosphate. This results in a reduction of activated farnesylated Ras.80
Illustrative of the potential of statin therapy, patients with primary liver cancer were treated with either the chemotherapeutic drug 5-FU or a combination of 5-FU and 40 mg/day of pravastatin.81 Median survival increased from nine months, among patients treated with only 5-FU, to 18 months when using 5-FU combined with the statin drug pravastatin (Pravachol). In 2008, German researchers studied the effects of pravastatin in patients with advanced liver cancer.82 One hundred thirty-one patients received chemoembolization alone, while 52 patients received chemoembolization plus pravastatin (20‒40mg). During the observation period of up to five years, 23.7% of the patients treated with chemoembolization alone had survived, compared to a 36.5% survival for the chemoembolization and pravastatin group. Median survival was 12 months for the chemoembolization only group, while the pravastatin group had a median survival of 20.9 months.
Statin drugs are known to deplete coenzyme Q10 (CoQ10) levels, therefore those taking a statin drug should supplement with CoQ10. For a detailed explanation, please consult the coenzyme Q10 section in the “Cancer Adjuvant Therapy” protocol.
Individuals with cancer should consider an immunohistochemistry test of their cancer tissue for mutated ras genes at Caris Life Sciences Laboratories (see Step One of this protocol), a recommendation the Life Extension first made in 1997. Life Extension strongly believes all cancer patients should undergo immunohistochemical testing to determine Ras status.
How to Implement Step Five
Ask your physician to prescribe one of the following statin drugs to inhibit the activity of Ras oncogenes:
- Mevacor (lovastatin)
- Zocor (simvastatin)
- Pravachol (pravastatin)
Note: Statin drugs may generate adverse side effects. Physician oversight and careful surveillance with monthly blood tests (at least initially) to evaluate liver function, muscle enzymes, and lipid levels are suggested.
In addition to statin drug therapy, consider supplementing with the following nutrients to further suppress the expression of Ras oncogenes:
- Curcuminoids (from a highly bioavailable turmeric extract): 200 – 400 mg daily
- Fish oil: 2,100 mg of EPA and 1,500 mg of DHA daily with meals
- Green tea; standardized extract: 725 – 1,450 mg EGCG daily
- Aged garlic extract: 2,400 mg daily with meals
- Vitamin E: 400 – 1,000 IU of natural alpha tocopherol along with at least 200 mg of gamma tocopherol daily with meals