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vitamin c via iv

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January 24, 2020,
by Lewis Cantley and Jihye Yun

The invention and isolation of vitamin C was probably the most essential advances in enhancing human vitamin. Scurvy, a extreme vitamin C deficiency illness characterised by weak point, lethargy, simple bruising and bleeding, was notably problematic for sailors on lengthy voyages through the sixteenth century, the place entry to contemporary vegatables and fruits was restricted. The truth is, scurvy was the main explanation for naval deaths between the sixteenth and 18th centuries, killing extra sailors than all battles, storms and different illnesses mixed. It wasn’t till 1747 that Scottish naval doctor James Lind demonstrated that consuming oranges and lemons cured and prevented scurvy. Nonetheless, it took scientists practically two extra centuries to establish the character of the healing substance contained in citrus fruits, now generally referred to as vitamin C. The seek for this elusive substance resulted in 1932 when Albert Szent-Gyorgyi, a Hungarian biochemist, remoted and recognized a 6-carbon carbohydrate, hexuronic acid, because the anti-scurvy issue. Shortly thereafter, Szent-Gyorgyi renamed it “a-scorbic acid”, a reference to its anti-scorbutic properties, and later went on to obtain the Nobel Prize in Physiology and Medication in 1937 for his discoveries. 

At present vitamin C is a well-liked dietary complement, and as a consequence of improved accessibility to fruits, greens and vitamin dietary supplements, incapacity and dying from scurvy are uncommon. Nonetheless, it’s value noting {that a} important variety of individuals even in developed international locations are nonetheless vitamin C poor. For instance, roughly 7% of the US inhabitants has a plasma vitamin C focus of lower than 11 μM, that’s thought of scurvy. Vitamin C has many important capabilities in our physique along with its well-known function as an antioxidant. Thus, extended intervals of sub-optimal vitamin C publicity may have opposed well being results, together with an elevated susceptibility to a plethora of illnesses. The truth is, the optimum dosage of vitamin C required to maximise its well being advantages has been hotly debated ever since its discovery a century in the past. Linus Pauling, a world-renowned chemist and two-time Nobel Prize Laureate, strongly advocated that megadose portions of vitamin C (above 1 g consumption per day) would forestall and deal with many diseases together with the frequent chilly and coronary heart illnesses. Nonetheless, mainstream drugs has largely ignored and even ridiculed Pauling’s declare. This controversy continues to be very a lot alive immediately.

 

The controversial historical past of high-dose vitamin C in most cancers therapy

Using excessive doses of vitamin C as a most cancers remedy isn’t any exception to this controversy. Practically 60 years in the past Toronto doctor William McCormick noticed that most cancers sufferers usually introduced with severely low ranges of vitamin C of their blood and featured scurvy-like signs, main him to postulate that vitamin C would possibly defend towards most cancers by rising collagen synthesis. In 1972, extending this concept, Ewan Cameron, a Scottish surgeon, hypothesized that ascorbate may suppress most cancers improvement by inhibiting hyaluronidase, which in any other case weakens the extracellular matrix and allows most cancers to metastasize. He started treating terminally in poor health most cancers sufferers and revealed a case report of fifty sufferers wherein a number of the handled sufferers benefited from excessive dose vitamin C. 

Inspired by the consequence, Cameron teamed up with Linus Pauling to conduct scientific trials involving terminal most cancers sufferers. In 1976, they revealed a examine of 100 sufferers with terminal most cancers handled with ascorbate. Their illness development and survival charges had been in comparison with 1000 retrospective management sufferers who had been matched with the vitamin C-treated sufferers concerning age, intercourse, kind of most cancers and scientific stage and who had been handled by the identical physicians in the identical hospital, and in the identical method besides that they didn’t obtain vitamin C. Though the examine was not properly designed by trendy requirements, primarily as a result of they lacked the placebo-control group, the outcomes demonstrated that sufferers handled with vitamin C had improved high quality of life and a four-fold enhance of their imply survival time. In a observe up examine, Cameron and Pauling reported that 22% of vitamin C-treated most cancers sufferers survived for a couple of yr in comparison with solely 0.4% of management sufferers. A scientific trial in Japan independently confirmed an analogous consequence. With these promising outcomes, curiosity within the potential of vitamin C for most cancers remedy grew. Nonetheless, double-blind randomized scientific trials directed by Charles Moertel of the Mayo Clinic failed to indicate any constructive results of excessive dose vitamin C in most cancers sufferers, as reported in two papers within the journal of New England Journal of Medication. As a result of the Mayo Clinic’s scientific trials had been carried out extra rigorously, individuals trusted the Mayo Clinic’s information and discredited the Cameron-Pauling trials, dampening the keenness for vitamin C as a most cancers remedy. 
So why did the Pauling and Mayo Clinic trials have completely different outcomes? There are at the very least two essential variations. First, the Mayo Clinic trials abruptly stopped the ascorbate administration, switching to conventional chemotherapy, when the affected person developed indicators of tumor development. Thus, the general median time of vitamin C therapy beneath the Mayo Clinic trials was solely 2.5 months, whereas the Pauling and Cameron trials handled sufferers throughout your complete examine interval or so long as 12 years. Secondly, the Mayo Clinic trials administered 10 g of each day ascorbate to sufferers solely orally, whereas the Cameron and Pauling trials administered their vitamin C each orally and intravenously. This distinction within the two dosage routes proved extremely consequential.

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Rekindling vitamin C most cancers remedy: oral vs intravenous administration  

Primarily based on research pioneered by Mark Levine’s group on the NIH within the 2000s, the oral vitamin C doses used within the Mayo Clinic research would have produced peak plasma focus of lower than 200 μM. In distinction, the identical dose given intravenously, as used within the Pauling research, would produce peak plasma concentrations of practically 6 mM, greater than 25 occasions greater. When given orally, vitamin C focus in human plasma is tightly managed by a number of mechanisms appearing collectively: intestinal absorption, tissue accumulation, renal reabsorption and excretion, and probably even the speed of utilization. Nonetheless, when ascorbate is run intravenously or intraperitoneally the tight controls are bypassed, and pharmacologic millimolar plasma concentrations of vitamin C can simply be achieved. For instance, a section I scientific examine revealed that ascorbate concentrations may safely attain 25-30 mM with intravenous infusion of 100 g of vitamin C. On this examine, plasma concentrations round 10 mM had been sustained for at the very least 4 hours which, based mostly on preclinical research, is enough to kill most cancers cells. Given the truth that most cancers sufferers had been solely handled with vitamin C orally within the Mayo Clinic research, the research don’t disprove excessive dose vitamin C’s efficacy as a most cancers therapy. 
This new information has rekindled curiosity and spurred new analysis into the scientific potential of vitamin C. Consequently, over the previous decade, there have been an elevated variety of section I/II scientific trials and case stories testing the security and efficacy of excessive dose vitamin C as a therapy for numerous most cancers sufferers as a monotherapy or in combinational remedy. We is not going to talk about these scientific research as there are already a number of opinions on the subject. Just about all research present improved high quality of life for most cancers sufferers by minimizing ache and defending regular tissues from toxicity attributable to chemotherapy. Moreover, vitamin C confirmed synergistic results when mixed with radiation and customary chemotherapies. Sadly, these research weren’t designed as large-scale, randomized managed trials and thus the efficacy of excessive dose vitamin C remedy stays to be decided.

 

Challenges of conducting a randomized managed trial for vitamin C most cancers remedy

There are at the very least three challenges which have up to now prevented large-scale, randomized managed trials of vitamin C for most cancers remedy. First, vitamin C will not be patentable. Subsequently, there isn’t a monetary incentive for pharmaceutical firms to assist vitamin C scientific trials, and people which have been achieved have largely relied on authorities grants and small non-public donations. Second, as mentioned above, vitamin C most cancers remedy has an extended historical past of controversy. As a result of Mayo scientific research within the Eighties, many orthodox, mainstream clinicians have a prejudice towards vitamin C remedy. Third, though many preclinical research confirmed excessive dose vitamin C may kill most cancers cells or retard tumor development in vivo, vitamin C’s mechanisms of motion haven’t been clear, making it arduous to foretell the pharmacodynamics, the rational design of combinational remedy, and biomarkers for affected person stratification. Thankfully, a rising variety of current and rigorous preclinical research have begun resolving the third problem, which can additionally result in overcoming the primary and second limitations. Mechanistic insights into the motion of pharmacological vitamin C will generate extra express scientific hypotheses and permit clinicians to design higher trials to analyze these hypotheses, in the end resulting in a definitive reply to the query: can the pharmacological administration of ascorbate profit most cancers sufferers? Lately, we mentioned the potential mechanisms by which vitamin C could act in most cancers sufferers in Nature Opinions Most cancers. Right here we’ll spotlight one of many mechanisms found by our group that pertains to Ras protein. 

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Excessive-dose vitamin C remedy for KRAS/BRAF mutant cancers

Greater than 80 years in the past, the biochemist Otto Warburg noticed that most cancers cells devour extra glucose and produce extra lactate even within the presence of ample oxygen as in contrast with regular cells. This phenomenon, known as cardio glycolysis or the Warburg impact, has been exploited for visualizing tumors within the scientific setting by imaging their uptake of the radiolabeled glucose analog, [18F] fluoro-2-deoxyglucose (FDG), by way of Positron Emission Tomography (PET). Though the precise mechanism by which glucose reprograming contributes to tumorigenesis stays unclear, quite a few genetic and pharmacological research confirmed that this metabolic swap may be important for most cancers survival and proliferation. Thus, focusing on glycolysis could provide most cancers sufferers a extra selective technique to deal with most cancers. 

Greater than half of colorectal cancers (CRCs) harbor activating mutations in KRAS or BRAF, but these cancers are essentially the most refractory to present focused therapies. Our group and others confirmed that oncogenic mutations in KRAS or BRAF contribute to the Warburg impact and the dependancy to glucose partly by upregulating a glucose transporter, GLUT1, that permits most cancers cells to take up glucose effectively. These information recommend a technique for focusing on KRAS or BRAF mutant most cancers by exploiting the selective expression of GLUT1 and the metabolic legal responsibility that comes with elevated reliance on glycolysis. Certainly, by focusing on these distinctive options in these most cancers cells, we lately confirmed that prime dose vitamin C may selectively kill KRAS or BRAF mutant CRC cells.
Apparently, GLUT1 not solely transports glucose but in addition transports dehydroascorbic acid (DHA), the oxidized type of vitamin C. Subsequently, we noticed that CRC cells harboring KRAS or BRAF mutations uniquely elevated uptake of DHA by way of GLUT1 when handled with vitamin C. The elevated DHA uptake in mutant cells produced oxidative stress, rising the extent of reactive oxygen species (ROS) in cells as a result of intracellular DHA was quickly decreased again to vitamin C on the expense of glutathione (GSH), a grasp antioxidant in cells. In flip, we discovered that elevated ROS activated poly (ADP-ribose) polymerase (PARP), a DNA restore enzyme, consuming massive quantities of mobile NAD+ as its cofactor. The depletion of NAD+ resulted within the inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a result of GAPDH requires NAD+ as a cofactor. Inhibiting GAPDH in extremely glycolytic KRAS or BRAF mutant cells in the end led to an power disaster and cell dying not seen of their KRAS and BRAF wild-type counterparts. Lastly, we confirmed that high-dose vitamin C remedy decreased each the quantity and measurement of tumors in KRAS or BRAF mutant mice as in comparison with mice with out these mutations, confirming that vitamin C selectively targets KRAS or BRAF mutant tumors in mouse fashions of colon tumors. In brief, ascorbate capabilities as a “Trojan horse” by its conversion to DHA, and insidiously enters most cancers cells by way of GLUT1 to advertise the era of intracellular ROS, which in the end kills the most cancers cell.

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Though our examine confirmed that DHA is the pharmaceutically lively agent, decreased ascorbate (circuitously DHA) is used for preclinical and scientific anti-cancer research as a result of ascorbate has a considerably longer plasma half-life than DHA (>60 min vs a number of min). Furthermore, the decreased ascorbate may be effectively oxidized to DHA in tumors’ extracellular fluids the place excessive stage of ROS often exists. On condition that KRAS and BRAF mutations should not solely restricted to colorectal most cancers, vitamin C could also be profit different varieties of tumors. For instance, 90% of pancreatic cancers and roughly 30% of lung cancers have KRAS mutations. These KRAS mutant tumors even have excessive GLUT1 expression and are linked to altered glucose metabolism much like CRC. Subsequently, excessive dose vitamin C could profit different varieties of tumors harboring KRAS/BRAF mutations. Primarily based on these outcomes, Weill Cornell Medication is at the moment conducting a Section II scientific trial to look at the results of intravenous excessive dose vitamin C within the therapy of KRAS-mutant cancers, and Solar Yat-sen College Most cancers Heart in China are conducting placebo-controlled, randomized Section III scientific trials in colorectal most cancers sufferers together of chemotherapy. 
Whereas KRAS and BRAF mutations are actually two of essentially the most ceaselessly mutated oncogenes in human most cancers, they don’t seem to be the one mutations identified to have an effect on glucose metabolism and sensitivity in direction of ascorbate remedy. For instance, we and others have discovered that renal most cancers cells (RCC) with lack of VHL (Von Hippel-Lindau), a tumor suppressor that destabilizes HIF1A by way of ubiquination, are considerably delicate to ascorbate therapy in comparison with VHL-proficient cells. RCC-VHL null cells have elevated HIF1A transcriptional exercise, which not solely will increase GLUT1 expression, but in addition deregulates many different glycolytic enzymes to induce metabolic reprograming. Moreover, cancers with elevated ranges of DNA harm, corresponding to these which have been handled with radiation or these with mutations in BRCA genes, are extra reliant on DNA restore mediated by PARP. Pharmacologic vitamin C would possibly selectively impair such cancers by depriving them of the NAD+ essential for PARP exercise.

 

Concluding Remarks – “vitamin c via iv”

Vitamin C as a most cancers remedy has had a controversial previous. What has been intriguing are small scientific trials that recommend some responses, however with no clear rationale for why cancers ought to reply to vitamin C or a path ahead for explaining which sufferers are most definitely to reply.  Now a rising variety of preclinical research are displaying how high-dose vitamin C would possibly profit most cancers sufferers. Importantly, these preclinical research present a transparent rationale and potential biomarkers that will assist personalize the therapeutic method and establish affected person populations which might be seemingly to reply to high-dose vitamin C remedy. For the reason that mechanisms of motion of vitamin C have gotten higher outlined, we will suggest vitamin C mixtures in a extra rational, hypothesis-driven method. As well as, given the present excessive monetary value of recent most cancers medication, it appears rational to enhance the effectiveness of present therapies by finding out their scientific interactions with vitamin C. In our view, the implementation of this therapy paradigm may present profit to many most cancers sufferers.

 

Acknowledgements 

This work was supported by the US Nationwide Institutes of Well being (NIH) grant (R35 CA197588), Stand As much as Most cancers–American Affiliation for Most cancers Analysis grant (SU2C-AACR-DT22-17), and the Damon Runyon Most cancers Analysis Basis. Lewis Cantley is a founder and member of the senior advisory boards of Agios Prescribed drugs and Petra Prescribed drugs, that are creating novel therapies for most cancers. The Cantley laboratory additionally receives monetary assist from Petra Prescribed drugs.

 

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