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Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Human Immune System in Health and in Disease, Nutrition | Tagged anaerobic respiration, Antioxidant, ascorbate, ascorbic acid, Cancer - General, cancer therapy, cell proliferation, cell viability, cellular ATP, Chemotherapy, coenzyme Q, collagen, dihydroascorbate, DNA, DNA damage, electron transport chain, glucose, glucose transporters, GLUT, hydrogen peroxide, KREBs cycle, lipid peroxidation, lipoic acid, malignant cells, mitochondria, NFkB, oxidant, peroxide damage, pro-oxidant, prostaglandins, Radiation, Reactive oxygen species, Ritu Saxena, scurvy, tocopherol, tumors, vitamin c, vitamin E, wound healing | 16 Comments

16 Responses

1. on January 15, 2013 at 10:55 AM | Reply tildabarliya

   Nice post!!! up to the beat.

   
   
   • on January 15, 2013 at 12:39 PM | Reply lbretes

     A very intelligent post,not to many words….but many things to think about….good news!!!Congratulations Dr Ritu!

     
     
2. on January 15, 2013 at 7:17 PM | Reply sjwilliamspa

   Dr. Ritu thanks for a thorough post on ascorbic acid (vitamin C) on both the por and con aspects as chemopreventative and chemotherapeutic. I think most of the world has been lulled into the any amount of antioxidant is good and so fights cancer. As I discussed with Dr. Berstein, there are just as many pro clinical trials as con clinical trials. As a way to teach high school students on the lesson “too much of a good thing can be bad” I had them treat cancer cells with increasing concentrations of ascorbic acid and showed at certain high concentrations cancer cell dies. The high concentrations may had also produced an intracellular acidosis but this was a simple but visual experiment. On another note I am glad you had talked about the prooxidant functions of vit C (same can be said about Vitamin A). Vitamins which are oxidized must be reduced or wind up becoming a radical themselves (like quinones). I did see that trial with the high i.v. AA for ovarian cancer but I think the trial needed to be bigger and there may have been complications. I’ll check on that

   
   
3. on January 16, 2013 at 1:41 AM | Reply mjg5

   Dear Dr Saxena: Excellent review! I’ll be glad to answer any questions on IV Vitamin C and Cancer that may arise.

   
   
4. on January 16, 2013 at 1:45 AM | Reply megbaker58

   Ritu, a word of caution about reviewing these old, old papers: Pauling was a physicist and organic chemist, not a biologist. 60 g of AA is 100-200X the minimum daily requirement. What he may have shown was that 30 mg is about enough to prevent scurvy and optimum daily intake is really several fold higher. As Dr. Williams points out, you can kill cancer cells by dousing them with lots of things, even green tea will work.
   By the way, lack of ascorbate will lead to loss of lysyl hydroxylase capacity (requiring AA plus Cu2+) resulting in decreased cross bonding of polypeptides of the triple helical structures in collagen fibrils. The resulting instability compromises the integrity of mucous membranes, causing dryness, cracking and then the invasion of foreign particles such as bacteria and viruses. This may be the main “immune defense defect” seen in Vit C deficienty, in the addition to the6 effect on leukocyte functions.
   Ascorbate is required for proper iron absorption and utilization as ferric iron (Fe3+) must be reduced to ferrous (Fe2+) for uptake then stored as ferritin (Fe3+) and mobilized for,e.g. heme (hemo- and myoglobins) and cytochrome biosynthesis by re-reduction. This may account for the “ergogenic” functions.

   Also, it is dehydroascorbic acid (DHA) not dihydroascorbic acid that is the oxidized form of the molecule.
   Once again, it’s all about keeping track of your electrons (and cofactors)!

   
   
   • on January 16, 2013 at 2:31 AM | Reply mjg5

     Dr. Linus C. Pauling (1901-1994) was one of the most brilliant scientists of the 20th century. Pauling was awarded the Nobel Prize for Chemistry in 1954. He also won the Nobel Peace Prize in 1962 for his campaigning against nuclear testing. Pauling is the only person to be awarded two unshared Nobel Prizes. In 1949, Pauling and his colleagues published a paper in Science that announced the discovery of the cause of sickle-cell anemia, the first disease to be described as a molecular disease. He had worked on hemoglobin for many years and published a number of papers on its properties. (In 1965, he and Emile Zuckerkandl published an extremely influential paper on the use of hemoglobin and other globin proteins to estimate the evolutionary divergence of organisms, which introduced the science of molecular evolution.) While serving as a member of the Medical Advisory Committee of the United States government in 1945, Pauling listened to Dr. William Castle of Harvard describe the abnormal sickle shape of the red corpuscles in patients with sickle-cell anemia. Pauling immediately suggested that the sickling might be caused by an abnormal hemoglobin that combined with itself into long rods when deoxygenated. The long rods then twist the red corpuscle into the abnormal shape characteristic in sickle-cell anemia. A few years later, Pauling was able to test and confirm this hypothesis with the help of Dr. Harvey Itano. Their Science paper, which demonstrated that sickle-cell anemia is caused by an abnormal molecule, heralded the era of molecular medicine. By the late 1950s, Pauling had become increasingly interested in the role of enzymes in brain function. Thanks to funding from the Ford Foundation, he started to explore the biochemistry and molecular basis of mental illness. He learned about changes in mental function that precede the overt B vitamin deficiency diseases—pellagra, pernicious anemia, and beriberi—and later learned about the work of two psychiatrists, Abram Hoffer and Humphry Osmond, who were reporting success in treating schizophrenics with niacin, the B vitamin that prevents pellagra. With the recognition that deoxyribonucleic acid (DNA) is the genetic molecule, Pauling became interested in its three dimensional structure. In 1953 he and Corey proposed that it was made up of three chains, twisted around each other in ropelike stands. Shortly thereafter, Watson and Crick proposed the double helix structure, which turned out to be correct. Watson and Crick had the advantage of X-ray photographs of DNA taken by Rosalind Franklin, an advantage denied Pauling because the U.S. State Department had lifted his passport. Orthomolecular medicine was created by Linus Pauling in an article published in the Journal of Science in 1968 titled “Orthomolecular Psychiatry.” This concept later was expanded by Dr. Linus C. Pauling and Dr. Abram Hoffer into the theory and practice of Orthomolecular Medicine.
     Do you still think he is not a biologist?
     Please read the paper discussed by Dr. Saxena, Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Integr Cancer Ther. 2005 Mar;4(1):32-44.

     
     
5. on January 16, 2013 at 3:57 AM | Reply ritusaxena

   Everyone, thanks for commenting on the post. Dr. Tilda, Dr. Bretes, Dr. Williams and Dr. Mjg, I am glad you liked the post.
   The paper reviewed in the post- Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Integr Cancer Ther. 2005 Mar;4(1):32-44, is an excellent review of the anticancer functions of vitamin C, mechanisms involved and also discusses the controversies surrounding it. There is vast amount of literature on the anticancer aspect of vitamin C and this paper emphasizes the key aspects.
   Dr. Meg, you have brought out an important point here- dose of vitamin C administered to the patients. I didn’t mention all the details of the experiments. It was observed from several experiments that only very high doses of AA such as that of 60g were observed to maintain a high plasma concentration in the cells that could bring about an increase in the selective uptake of vit C in cancer cells (mechanism explained in the post) leading to an increase in its concentration hence causing anticancer effects. Anyway, the point here is that 30g might be enough to cure scurvy because, as you mentioned, that is around 100-200 times more than the recommended dose, however, here the authors discussed the anticancer effects and hence the dose, route (intravenous) and time of administration were chosen. Also, combined administration of lipoic acid along with Vit C reduces the dose requirement significantly (also mentioned in the post). I hope I have made my point.
   Dr. Mjg, thanks for an expanded and beautifully written introduction of Pauling’s work as a biologist, chemist; looks like he contributed to several other fields. You are the expert of the field and we would love to have your perspective on the topic of vitamin C and cancer, the unanswered questions and the recent advances on the topic.
   Ritu

   
   
   • on January 16, 2013 at 10:39 PM | Reply Michael

     Thank you Dr.Saxena, the paper in discussion was published by our research group (RECNAC 2) as an update of the classical paper published by Dr. Linus Pauling, Dr. Ewan Cameron and Dr. Brian Leibovitz in 1979 in the journal Cancer Research entitled Ascorbic acid and Cancer. Ascorbic Acid and Cancer 25 years later has been one of the most read papers on the subject. It is an honor to follow the steps of these giants.

     
     
6. on January 16, 2013 at 8:52 PM | Reply larryhbern

   i watched a lecture by Linus Pauling on public TV as a child. He was incredible. I would never dismiss him as just a physicist and organic chemist.
   His Nature of the Chemical Bond is a classic. It was fundamental to giving greater clarity to the molecular orbital structure involved in chemical bonding.
   Pauling was very sensitive to allergies, and his secretary protected him. That may have been a factor in his interest in vitamin C.

   Albert Szent-Geogyi was a Hungarian biochemist who studied with Otto Warburg along with Hans Krebs. They both received Nobels, but Szent Gaorgyi purified AA from ‘hungarian paprika’. My mother made chicken and veal paprikash that was better than we had in Budapest. It turns out that Pauling was a good friend of Seymour Beckman, who brought out the Beckman DU spectrophotomer (that I used) and a fluorometer (tht I used).

   He had flown during WWII and knew the underlying principles of the instruments.. He had a neighbor who had bad lemons and wanter help fixing the problem. That gave rise to the pH meter. The neighbor acme back for another pH meter because his neighbor borrowed it and kept it. So Beckman travelled the country to find out the need for this instrument, and the pH meter was born. Both Pauling and Beckman live to 100 years.

   Harvey Itano was one of my teachers at UCSD, and so was Kurt Benirschke, who did all of the placentas. He was Scientifc Director of the San Diego Zoo.
   I’ll never forget his proof that the fastest horse in the world, the Prazawarky Horse in Russia, is not a horse! We had “Baby Pauling from Riverside give a seminar while I was with Kaplan’s group.

   I didn’t realize that in the historic race to the DNA structure, Pauling had a Triplex model, that turned out to be wrong. Significant research has gone on that rejects the Watson-Crick model as the final model BECAUSE it doesn’t take enough into account for a full explanation. There are other substances needed for a refined triple helix, such as inosine. I have several of the papers and have been in contact with a scientist in Chicago, who has made a lot of headway.

   mjG5 has provided good material that I downloaded. I think he or Martin Canizares has a paper coming out very soon.

   This is where science differs from religion. We are always trying to get evidence to support, or to put limitations on our hypotheses.

   There is discussion these days about scientific fraud. I spent enormous hours in purification to find that there is not a proposed residue at the active sight of the DPN dependent mMDH, which caused a Johns Hopkins Professor to retract several of his papers.

   
   
7. on January 17, 2013 at 9:59 AM | Reply megbaker58

   Linus Pauling was a brilliant and tireless researcher. His approach to medicine was through his understanding of chemical and biochemical structures and electronic interactions. I had forgotten his work on sickle cell hemoglobin and attempt at solving the structure of DNA. I thank Dr. Larry for bringing up Albert Szent-Geogyi, a true pioneer in understanding of the role of Vitamin C and many other vitamins in good health. He lived for many years in the USA and founded the National Foundation for Cancer Research (NFCR). Like Pauling, he sought to understand the electronic interactions between biomolecules. Treatment of pellagra and beriberi with and their associated mental symptoms by restoring adequate thiamin and niacin, respectively, levels to the diet has been practiced since the turn of the 20th century and why rice and cereals are generally “fortified” with thiamin. In the ‘70s, the concept of “orthomolecular medicine” became synonymous with megadose vitamin therapy. An interesting current development is that an NIH trial of Abbott’s megadose niacin (1000 mg) product, Niaspan, showed no benefit over a statin alone in reducing cardiac events and stroke although it has been proven to raise HDL and lower triglycerides (data first demonstrated 30 years ago in the laboratory).
   Thanks Dr. Ritu, for clarifying that the positive effects of megadose Vit C were seen in some patients given i.v. therapy and that the mechanism of response is still not understood. I could not access the review except for the abstract but found another available on-line which clarified the situation: Ohno at Anticancer Research Mar 2009 http://ar.iiarjournals.org/content/29/3/809.long
   As one of the citations therein http://www.jacn.org/content/19/4/423.full points out – it is good to have an open mind and pursue science with rigor.
   Please correct dihyro to dehydro
   Thanks

   
   
   • on January 18, 2013 at 7:57 PM | Reply Michael

     There are a series of pleiotropic events that follow high dose IV Vitamin C. Nevertheless the main anticancer mechanism resulting from this therapy is the formation of hydorgen peroxide. Most cancer cells lack catalase which make them very susceptible to H2O2.

     
     
8. on January 18, 2013 at 5:51 PM | Reply 2012pharmaceutical

   Dr. Ritu,

   Many thanks for your very inspiring post On Cancer and Vitamin C. The discussion is outstanding.

   One suggestion, I would have started the post with the the following two sections:

   Classical vitamin C and Cancer controversy-A possible explanation
   Modern vitamin C and Cancer controversy-Chemotherapy and radiation

   Please review, below

   Linus Pauling: On Lipoprotein(a) Patents and On Vitamin C

   With the results of their Lipoprotein(a) [LP(a)] experiments in hand, Linus Pauling and Matthias Rath decided to create a treatment and try to patent it. Their treatment relied on three main ideas: First, that increased Vitamin C levels in the bloodstream would prevent the creation of lesions to which Lp(a) might bind. Second, that lipoprotein binding inhibitors would detach any plaque that had already built up. And lastly, that Vitamin C would then also help the body to filter out Lp(a). In this way, it could be used to both treat and prevent cardiovascular disease (CVD) and other related cardiovascular problems.
   The duo also saw great potential use for their research in surgery – specifically angiopathy, bypass surgery, organ transplantation, and hemodialysis. Lysine or other similar chemicals naturally help to speed the healing process and also act as blood clotting agents, therefore reducing the risk of blood loss during surgery. Also, patients undergoing organ transplant surgery, bypass surgery, and hemodialysis often suffer strong recurrences of CVD, which Pauling and Rath felt was due to depleted Vitamin C levels from blood loss. Similarly, diabetics often suffer from both inhibited Vitamin C absorption and higher levels of Lp(a), leading Pauling and Rath to hope that their work could help to treat diabetes-related CVD as well.
   When living patients were using their treatment, the mixture was designed to be taken orally in pill or liquid form, or injected intravenously. Pauling also wondered if the mixture could be taken subcutaneously (injected into the deepest level of skin), percutaneously (injected into internal organs), or intramuscularly (injected into the muscle). When being used as preparation for transplant surgery, the organs to be transplanted were to be soaked in the mixture. Later research done by other scientists showed that Vitamin C is not absorbed into the bloodstream like it was thought, and that there are specific Vitamin C carrier molecules in the digestive tract, therefore limiting the amount of Vitamin C a person can absorb when taken orally. As such, injection is a much more effective method of getting Vitamin C into the bloodstream.
   Pauling and Rath’s work was polarizing, if not unprecedented. As far back as the early 1970s, enthusiastic support for Vitamin C by Pauling and others had been a point of extreme controversy. Now, even with this latest batch of research, many scientists and doctors seemed to think that their conclusions were grossly incorrect, and in some cases even dangerous for people. Pauling, Rath, and their supporters felt that the harsh criticism emerged, at least in part, from pharmaceutical companies concerned about losing revenue if people stopped buying their expensive medications and instead bought inexpensive, common Vitamin C. On the flip side, many of the people who felt that their research was correct were absolutely steadfast in their support.
   The controversy surprised Pauling. He repeatedly expressed these feelings, pointing out that he was not the first to make claims about the benefits of Vitamin C nor even the most extreme, and yet he was viewed as a controversial figure espousing fringe medicine. The Pauling-Rath team was not the only organization researching and promoting the positive effects of Vitamin C. Other groups, such as that led by Dr. Valentin Fuster of Harvard Medical School, were conducting similar experiments. Pauling and Rath attempted to collaborate with them where possible, often with success. But more generally the duo had to rely heavily upon individual case histories to support their research, largely because they were unable to convince major American institutions to conduct their own studies or to sponsor the Linus Pauling Institute of Science and Medicine’s studies.

   Figure 1 from Pauling and Rath’s July 1990 patent application.

   On July 27, 1993, Pauling and Rath were awarded a patent for the application filed in April 1990. On January 11, 1994, they received a second patent for the application filed in July 1990. Shortly afterward, in March 1994, the two filed a third application, following similar grounds, titled “Therapeutic Lysine Salt Composition and Method of Use.” The compound they were patenting was a mixture of ascorbate, nicotinic acid (also known as Vitamin B3 or niacin) and lysine, or a lysine derivative. The mixture was to be combined at a ratio of 4:1:1, and include a minimum of 400 mg of ascorbate, 100 mg niacin and 100 mg lysine. The mixture functioned more or less identically to the previous two patents, the major difference being the inclusion of Vitamin B3 for its antioxidant properties. Pauling and Rath also encouraged the inclusion of additional antioxidant vitamins.
   This was the last patent that Pauling and Rath would file together. Shortly afterward the two experienced a falling out and Rath left LPISM.  A few months later, on August 19, 1994, Linus Pauling passed away from cancer.
   The third patent application was approved and awarded to Pauling and Rath in 1997. The two hadn’t made any profit off of the previous patents to speak of, and research that followed in the later 1990s and after 2000 showed that Vitamin C appeared to have no real effect on Lp(a). The discrepancy between the Pauling-Rath trials and subsequent tests seem to be attributable to the major differences between the two test subjects – humans and guinea pigs. However, other trials have shown that large doses of Vitamin C are useful in fighting cardiovascular disease – for reasons other than Lp(a) levels – and also work to combat stroke, decrease blood pressure and provide other health benefits.
   Additional studies in the wake of Pauling and Rath have also revealed the complexity of Lp(a).  The compound is today regarded to be somewhat of a mystery in terms of function, as scientists aren’t very clear on what it does in the human body. Also, “normal” levels of Lp(a) vary massively on an individual basis, a trait that seems to trend along racial lines. As a result, choosing Lp(a) as a target for medication has proven to be extremely difficult.

   http://paulingblog.wordpress.com/tag/lipoproteina/

   https://pharmaceuticalintelligence.com/2013/01/18/linus-pauling-on-lipoproteina-patents-and-on-vitamin-c/

   
   
9. on January 20, 2013 at 10:48 AM | Reply Linus Pauling: On Lipoprotein(a) Patents and On Vitamin C « Pharmaceutical Intelligence

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