The K-Ras protein plays important roles in cell signaling pathways that control cell growth, cell maturation, and cell death. Mutations in the gene that codes for this protein have been associated with increased risk for various types of cancer. Non-small cell lung cancer, colorectal cancer, and pancreatic cancer have each been associated with mutated forms of the KRAS gene. Non-small cell lung cancer and pancreatic cancer can be difficult to treat and the prognosis can be poor; however, research is shining light on an adjunctive combination therapy that may significantly delay tumor progression. [1] This combination therapy, which has been associated with very minimal side effects, includes a fasting-mimicking diet and intravenous vitamin C.
What exactly is the KRAS gene?
The KRAS gene codes for the K-Ras protein, an oncogene that plays a critical role in cell division, cell differentiation, and cellular apoptosis. [2] This protein is a part of the RAS/MAPK pathway, and it conveys extracellular proliferation- and differentiation-related signals to the cell’s nucleus.
How does the KRAS gene affect cancer risk?
As an oncogene, mutations in the KRAS gene can lead to healthy cells becoming cancerous. So far, researchers have discovered at least three mutations in the KRAS gene that are associated with increased risk for lung cancer. As previously discussed, mutations in the KRAS gene have also been associated with pancreatic and colorectal cancer.
The mutations in this protein tend to be substitutions that change the glycine at position 12 or 13 of the protein or the glutamine at position 61 in the K-Ras protein. [2] The result is a constitutively activated protein that consistently tells cells to proliferate. This, of course, can lead to tumorigenesis.
How might IV vitamin C and the fasting mimicking diet help with KRAS-mutated pancreatic and non-small cell lung cancer?
Fasting-mimicking diets have been demonstrated to decrease the rate of tumor progression, sensitize various types of cancer to chemotherapeutic agents, and protect normal cells from the adverse effects associated with chemotherapeutic agents. [3,4] However, until fairly recently, neither their mechanism of action nor their therapeutic potential when not utilized in combination with chemotherapeutic agents were well understood. Researchers recently demonstrated in vitro and in animal models of KRAS-mutated cancers that combining fasting-mimicking diet cycles with pharmacological doses of vitamin C selectively potentiates the antineoplastic effect of vitamin C against KRAS-mutated tumors by counteracting vitamin C’s upregulation of heme-oxygenase-1.
Essentially, although vitamin C is well-documented as having antineoplastic effects, its anticancer activity is limited by the fact that it upreglates heme-oxygenase-1. By reversing this upregulation, as well as the upregulation of ferritin in KRAS-mutated cancer cells, fasting mimicking diets enhance the anti-cancer effects of vitamin C, and these effects are further potentiated by chemotherapeutic agents.
In short, when used in combination, pre-clinical research suggests that fasting mimicking diets and vitamin C may lead to delayed tumor progression in cases of KRAS-mutated cancer cells and even disease regression in some cases of KRAS-mutated cancers.
What does a fasting mimicking diet entail and how does one adopt this type of diet?
As typically practiced, the fasting-mimicking diet is a 5-day eating pattern that involves consuming macronutrients and micronutrients in precise quantities and combinations. The desired result is for the body physiology to mimic a fasting state, such that the physiological occurrences that take place while on a water-only fast (such as ketosis, for example) actually occur in spite of the person eating meals.
In order to achieve this desired end result, people typically consume 25% of their typical caloric intake for two days and they consume a more typical amount of calories for 3 days. The days within the 5-day period where the caloric intake is decreased do not necessarily have to be contiguous; they can be days 2 and 5, for example.
These 5-day eating patterns are typically repeated for multiple cycles. There are meal kits that people can purchase in order to get the specific macro- and micronutrient ratios that are required for a successful fasting-mimicking diet. There are also ways to do this while eating whole food.
Conclusion
In conclusion, research suggests that the combination of the fasting mimicking diet and pharmacological doses of vitamin C may help delay tumor progression and even lead to disease regression in KRAS-mutated cancers, such as some cases of non-small cell lung cancer, pancreatic cancer, and colorectal cancer. Fasting mimicking diets have been demonstrated to enhance the anti-cancer effects of vitamin C, and these effects are further potentiated by chemotherapeutic agents. As a result, this combination therapy may be beneficial in difficult-to-treat KRAS-mutated cancer.
[1] Di Tano, M., Raucci, F., Vernieri, C., Caffa, I., Buono, R., Fanti, M., Brandhorst, S., Curigliano, G., Nencioni, A., de Braud, F., & Longo, V. D. (2020). Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nature communications, 11(1), 2332. https://doi.org/10.1038/s41467-020-16243-3
[2] U.S. National Library of Medicine. (2020, August 18). KRAS gene: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/gene/kras/#references.
[3] Raffaghello, L., Lee, C., Safdie, F. M., Wei, M., Madia, F., Bianchi, G., & Longo, V. D. (2008). Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 105(24), 8215–8220. https://doi.org/10.1073/pnas.0708100105
[4] Lee, C., Raffaghello, L., Brandhorst, S., Safdie, F. M., Bianchi, G., Martin-Montalvo, A., Pistoia, V., Wei, M., Hwang, S., Merlino, A., Emionite, L., de Cabo, R., & Longo, V. D. (2012). Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Science translational medicine, 4(124), 124ra27. https://doi.org/10.1126/scitranslmed.3003293