IMPACT OF HIGH-DOSE INTRAVENOUS VITAMIN C ON CANCERS WITH BRAF & KRAS MUTATIONS
As soon as someone talks about winter, oranges are the first thing that comes into mind. These citrus fruits not only taste amazing but the vitamin C present in oranges has been found to have the potential to fight cancer. Scientific research suggests that when vitamin C is given through the intravenous route in high doses, it can act as a very powerful anti-cancer agent. In our body, many essential functions for example growth of cells, etc., are controlled by proteins, and the information to form a protein is present in genes. The function of proteins changes when mutations in genes occur. Some of these genetic mutations alter proteins in such a manner that results in the modification of healthy cells into cancerous ones.
The two gene mutations that have been studied to observe the influence of high-dose intravenous vitamin C are the BRAF and KRAS genes. But before talking about how high-dose intravenous vitamin C work against BRAF and KRAS mutations, we will first look into what are these mutations and how they result in cancer formation.
WHAT ARE BRAF AND KRAS MUTATIONS?
The BRAF gene takes part in the formation of a protein known as BRAF. This protein is involved in cell growth by fulfilling an essential role in the conveyance of signals inside the cell to promote cell division along with many other functions (1). The changes in the BRAF gene due to mutation impair its working. The mutation in the BRAF gene results in the continuous production of protein causing a constant delivery of signals to cells to keep dividing and multiplying. But no instruction is delivered to cells on when to stop this multiplication. The outcome of continuous cell growth can be tumor development (2).
Cancer can be caused by BRAF mutations along with other factors or mutations and can result in the more rapid growth of cancer. The gene mutation in BRAF is not associated with cancer of one part or cell type. Cancers resulting due to BRAF mutation include hairy cell leukemia, almost half of melanomas, thyroid cancer, Non-Hodgkin lymphoma, colorectal cancer, lung adenocarcinoma, and certain cancers of the brain including pilocytic astrocytoma, glioblastoma, and low-grade glioma in children (2).
KRAS is another gene that takes part in the production of the proteins involved in the signaling pathways of cells to control the growth, maturation, and death of cells. The gene was named KRAS because it was the first time identified in Kirsten RAt Sarcoma virus as a reason behind cancer. When the KRAS gene is unchanged and natural, it is known as wild-type KRAS. The cells with KRAS mutation start producing large quantities of a protein named GLUT1. This protein is responsible for glucose transport across the membrane of cells. In this way, nutrients in high amounts are supplied to the cancer cells for their survival. The mutated KRAS gene has been found in colorectal cancer, non-small cell lung cancer, and pancreatic cancer (3).
FIGHTING THE BRAF AND KRAS MUTATIONS WITH HIGH DOSE INTRAVENOUS VITAMIN C
Numerous initial research in the start have reported that when vitamin C is used in high- doses, it is effective in raise the survival rate of patients suffering from advanced cancers (4–6). The therapeutic influence of vitamin C, when administered in high doses is dependent on the route of administration (7). Recent research demonstrated that when vitamin C is administered intravenously to achieve pharmacologic concentrations in plasma, it is able to selectively destroy the KRAS or BRAF mutant cells in colorectal cancer by way of targeting Glyceraldehyde 3 Phosphate Dehydrogenase (GADPH). (8) It is an enzyme that is required for creating energy through the breakdown of glucose.
HOW DOES HIGH-DOSE INTRAVENOUS VITAMIN C WORK AGAINST BRAF OR KRAS MUTATION?
The metabolic demands of cancer cells are met by glucose. To have a constant supply of glucose to meet their needs, cancer cells gather a large number of sodium and glucose transporters on the surface of their cells. Vitamin C (C6H8O6) has a structural similarity with glucose (C6H12O6) and this is what plays an important role. When a high dose of vitamin C is given through an intravenous route, it is oxidized to form dehydro-ascorbic acid (DHA).
If you can recall, KRAS and BRAF mutated cells increase the production of GLUT1 responsible to transport glucose inside the cell. The same GLUT1 transporter protein takes up the DHA instead of glucose and transports it into the mutated cells.
In the presence of nicotinamide-adenine-dinucleotide (NAD) phosphate and glutathione, the reduction of DHA into ascorbate (a form of vitamin C) takes place inside the cell. This decreases the antioxidant quantity inside the cell because all the antioxidants inside the cell get used up converting DHA into ascorbic acid and increasing the ROS level. We have already discussed ROS in our previous article.
GAPDH is inactivated in the existence of a high ROS concentration and instead, ROS activates poly (ADP-ribose) polymerase. It reduces NAD+ which acts as a cofactor of GAPDH. Hence, the outcome is blockage of GAPDH in those KRAS or BRAF mutant cells that are high in glucose content. When there’s a deficiency of GAPDH there is less conversion of glucose into energy and cell death occurs due to an energy crisis (9).
WHAT DO THE SCIENTIFIC STUDIES SAY ABOUT THIS IMPACT ON CANCER?
Among cancers caused by KRAS or BRAF mutation, colorectal cancer comes on the second number as the cancer causing most deaths globally (10). Activating BRAF mutations are observed in ten percent of colorectal cancers while forty percent of activating KRAS mutations are also observed in colorectal cancers in humans (11). A pivotal study observed the effect of administrating high doses of vitamin C intravenously in patients with colorectal cancer. They suggested that the pharmaceutically active agent, in this case, is the DHA, the oxidized form of vitamin C which selectively acts upon KRAS and BRAS through GLUT1 inhibition. The study also affirmed that when given intravenously, vitamin C attains the pharmacologic concentrations in the plasma to work efficiently (8).
Taking into account the inhibition of KRAS or BRAF mutant cells in colorectal cancer, another scientific research studied the influence of vitamin C on GLUT1 formation in cell lines of thyroid cancer (12). Thyroid cells showed that the GLUT1 formation was very high in the majority of the cell lines. This is consistent with what previous research said that thyroid cancer cells have an increased rate of glycolysis requiring high amounts of glucose (13,14).
The same study also investigated the viability of thyroid cancer cells in presence of vitamin C under a physiologic concentration of glucose in six millimolar. Cell viability indicates the number of healthy cells in a sample and their proliferation. The study reported that the cell viability was inhibited in both wild-type and BRAF mutant thyroid cancer cells. The study also observed when the glucose concentration of the medium was that is 2 millimolar, the sensitivity of thyroid cancer cells was more for vitamin C treatment in comparison to a high concentration of glucose (10 millimolar) (12). This was again consistent with the previous research (8).
The same study also reported that regardless of the mutation status of BRAF in thyroid cancer cells, the inhibitory action offered by the vitamin C of treatment that is dependent on dose was evident under physiologic concentrations of glucose (12). Earlier studies have demonstrated that human plasma concentration of vitamin C higher than two millimolar can be achieved without inducing any significant toxicity (7,15,16), the study showed that thyroid cancer cells can be killed with two millimolar concentrations of vitamin C (8). All these observations indicate that vitamin C can be safely used in treating thyroid cancer.
WHAT THE FUTURE HOLDS?
Scientists are studying the influence of high-dose intravenous vitamin C on various types of solid tumors including pancreatic cancers. The objective is to determine the tumor response after a high-dose infusion administration of vitamin C in patients suffering from lung, pancreatic, and colorectal cancer. A clinical study has been deliberated to check the efficacy and safety of administrating vitamin C to treat cancers with KRAS mutation. The clinical trial aims to detect the patients responding to the treatment, get more information about the mechanisms involved in producing the response, and collect scientific evidence providing clinical benefit.
Scientists hope and expect to see a decrease in the size of the tumor in those patients with BRAF and KRAS mutations. Another good response scientists expect is an increase in time for the disease to progress or stable disease for longer durations. The clinical trial also aims to look at the activity of RNA in the tumors to conclude that the lab findings can be correlated with the actions of vitamin C administration in patients. If the present trial bears positive results, it opens new horizons for the previously untreated population. Who knew that a very tasty fruit could hold such an ingredient that can change the course of cancer treatment. The scientists hope that the present clinical trial can inspire the medical field to gain a fresh perspective of this inexpensive and safe natural molecule.
REFERENCES
1. Peyssonnaux C, Eychène A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001 Sep;93(1–2):53–62.
2. Hussain MRM, Baig M, Mohamoud HSA, Ulhaq Z, Hoessli DC, Khogeer GS, et al. BRAF gene: From human cancers to developmental syndromes. Saudi J Biol Sci. 2015 Jul 1;22(4):359–73.
3. Jančík S, Drábek J, Radzioch D, Hajdúch M. Clinical Relevance of KRAS in Human Cancers. BioMed Res Int. 2010 Jun 7;2010:e150960.
4. Cameron E, Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact. 1974 Oct;9(4):285–315.
5. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3685–9.
6. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4538–42.
7. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533–7.
8. Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015 Dec 11;350(6266):1391–6.
9. Rangarajan S, Sunil B, Curtis L. Ascorbic Acid in Cancer: A Renewed Hope. J Cancer Sci Ther. 2014 Oct 1;333–6.
10. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7–33.
11. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004 Dec;4(12):937–47.
12. Su X, Shen Z, Yang Q, Sui F, Pu J, Ma J, et al. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics. 2019 Jun 9;9(15):4461–73.
13. Jóźwiak P, Krześlak A, Pomorski L, Lipińska A. Expression of hypoxia-related glucose transporters GLUT1 and GLUT3 in benign, malignant and non-neoplastic thyroid lesions. Mol Med Rep. 2012 Sep;6(3):601–6.
14. Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012 Jun;23(4):352–61.
15. Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139–46.
16. Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol Off J Eur Soc Med Oncol. 2008 Nov;19(11):1969–74.