The theme of this discussion is ascorbic acid and cancer intervention, including the etiology of cancer.

EXCERPT ONE:

Neoplasm, the medical terms for cancerous tumor is the uncontrollable rapid proliferation of abnormal cells that defy differentiation. According to Van Meter & Hubert (2014), cells are the functional units of the organism. Cells vary according to their degree of differentiation and organized tissue arrangement for specific biological functions. However, when cells become disorganized, undifferentiated, uncontrollable, and rapidly proliferating, there is loss of their specialized functions resulting in benign or malignant tumor that is no longer responding to body physiological processes (Van Meter & Hubert, 2014).

A benign tumor is characterized by differentiated cells. However, the cells are replicating similar to normal cells. The tumor is in situ or encapsulated without metastasizing. Often benign tumors are not bothersome, except putting pressures on adjacent organs and the resultant discomfort, including pain thus, the need for excision. Contrary to the unthreatening characteristics of benign tumors, malignant tumors are the dreaded culprits. The cells are undifferentiated while replicating rapidly.

Nevertheless, these malignant cancer cells infiltrate or metastasize into adjacent tissues and organs, including systemic spread throughout the body and become life-threatening (Van Meter & Hubert, 2014). Cancer cells deplete the body of its nutrient supplies resulting in lethargy and apathy of the body in protecting itself. Tumors are named using suffixes to denote whether tumor is benign or malignant, and prefix to present tissue of origin. The suffix, -oma for benign, and suffix carcinoma for epithelial tissue origin, and sarcoma for connective tissue origin that includes the bone, fat, muscle, blood, and cartilage. For example, whereas lipoma, a tumor of the adipose tissue is benign, liposarcoma, another tumor of the adipose tissue is malignant; osteosarcoma is the malignant tumor of the bone tissue.; adenocarcinoma is the malignant tumor of the gland etc.

 However, there are some exceptions to this cancer terminology rule. Example, leukemia is the cancer of the connective tissue (white blood cells) with specialized terms (Jones, 2003). There is international consensus on the nomenclature and taxonomy of leukemia. The international consensus classification (ICC) of leukemia references recent diagnosis, cytogenic, and molecular data with emphasis on gene expression in its taxonomy of leukemia (Borowitz etal, 2023). Different types of leukemia include B-Acute Lymphoblastic Leukemia, T-Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia with different lymphocyte subtypes. The most common type of leukemia is Acute Lymphoblastic Leukemia (Ameri etal, 2021).

According to Cameron etal (1979), host resistance to carcinogenic growth and metastasis is a significant factor in evaluating the diagnosis and prognosis of every neoplasmic condition. It’s well recognized that compromised immune system succumbs to diseased condition much easier than someone with intact or full-fledged immune system. Hence, the corollary is the case that natural resistance of the patient is crucial in predicting the prognosis of cancer illness. According to Cameron etal (1979), repertoire of theoretical and practical evidence indicating that the availability of ascorbate is the precursor to alleviating and potentiating various aspects of the host immunity to cancer. The history of Vitamin C is a common knowledge, according to Cameron etal (1979). In the middle of the 18th century, James Lind portrays that the aqueous liquid extract of fresh citrus fruits cures scurvy, a gum disease that is secondary to ascorbic acid deficiency.

 The active ingredient in this juice squeeze is the Enolic form of 3-Keto-L-Gulofuran-Lactone, also known as ascorbic acid or Vitamin. Enolic is isolated citrus juice in early 20th century by Albert Szent-Gyorgyi. By the middle of the third decade of the 20th century, methods have been invented to synthesize this compound. And henceforth, it becomes commonly available at a very low cost. Further, the safety and non-toxicity at any given dosage are established. It’s well documented that scurvy patients respond effectively to ascorbic acid therapeutic. Considering that the generalized stromal alterations in  scurvy is similar to the local stromal alterations detected next to the invading tumor cells, as revealed by Dr. William McCormick of Toronto in Canada.

 He hypothesizes that the nutrient, Vitamin C accepted to be effective in preventing such generalized alterations in scurvy can have similar effects in cancer. Also, the evidence that cancer patients experience Vitamin C deficiency validates the hypothesis. Also, there is the epidemiological inverse correlation between cancer incidence in large population groups and average daily Vitamin C consumption. Also, the anti-oxidant properties of Vitamin C observed in other antioxidants indicates that it has other anti-cancer effects (Cameron, etal, 1979).

According to Buettner etal (2012), ascorbic acid or Vitamin C functionally implies antiscorbutic properties due to its role in the synthesis of collagen. Available pharmacokinetic data show that intravenous administration of ascorbate circumvents the compact control of the gut thereby, generating highly increased plasma concentration. In very high plasma concentration of ascorbate, it elicits prodrug effect to deliver a substantial flux of H2O2 to tumor. This new knowledge about ascorbic acid has ignited attention to new research studies about the pharmacotherapeutic potential of ascorbate. However, understanding the mechanisms of action of pharmacotherapeutic ascorbate validates the rationale for its use in therapeutic intervention especially, intravenous administration as adjuvant in cancer pharmacotherapy.

 According to Buettner etal (2012), when ascorbate is administered intravenously, high plasma concentration is achieved, which is the effective pharmacological level. Also, according to Salaman (1998), antioxidants such as Vitamin C, Vitamin E, and Beta-Carotene in vegetables and fruits protect cells from damage by free radicals. She reiterates that free radicals are suspected to induce many cancers (Salaman, 1998).

 Also, to prevent cancer, Salaman suggests maximizing ascorbic acid dosage to the extent tolerable by individual bowel. She suggests starting the first day with 1000 mg hourly until diarrhea occurs. Then, start reducing the dosage. Vitamin C is non-toxic hence, maximum tolerable plasma concentration should be maintained daily for maximum benefits. Three or four times daily are recommended (Salaman, 1998). According to Head (2004), the mechanisms of action of ascorbic acid in the prevention and treatment of cancer involve the enhancement of the immune system, transduction of collagen generation necessary for confining tumors in situ, inhibition of hyaluronidase that maintains the adherence of the tumor thereby, preventing metastasis.

 Control of cancer viruses, restoration of healthy ascorbate concentration in plasma, potentiating the effects of cancer chemotherapeutic drugs, neutralizing the toxicity of other chemotherapeutic agents etc. Ascorbic acid is readily available in plant sources. Whereas some animals can synthesize ascorbic acid, humans cannot. Thus, it’s obtained from diet. Hydroxylation reactions are necessary for collagen synthesis. Again, collagen is necessary for walling off the tumors thereby, preventing metastasis.

Meanwhile, Alenar etal (2015), asserts that there are individual variations in dose response to ascorbic acid treatment, adding that this individual response to drug is associated with the mechanisms of action of the drug, Vitamin C. Another research study by Ai etal (2023), concludes that ascorbic acid has anticancer effect when administered in high dosage. However, its mechanisms of action under high plasma concentration remain unclear.

 Majeed etal (2021) writes that ascorbic acid has played a very significant role in anti-cancer drug development, adding that by inhibiting the  advancement of cancer through different  mechanisms of action,  including scavenging on reactive oxygen species (ROS), selectively generating ROS and facilitating their cytotoxicity,  preventing glucose metabolism, promoting  epigenetic  modulation, and  regulating the expression of hypoxia inducible factor  (HIF), with the critical functions of  glucose transporters (GLUTs), and Ten-Eleven translocation (TET). According to Majeed etal (2021), mutation and altered expression of TET protein families lead to abnormal DNA methylation that is important in cancer formation.

 Also, TET functions by elevating the suppression of tumor suppressor gene (SMATDi). In terms of HIF, the constant deprivation of oxygen in cells induces HIF that mutates the expression of various genes, leading to angiogenesis and the formation of erythrpoietic stem cells. According to Greijer & Vanderwall (2004), apoptosis can be triggered in response to hypoxia. HIF-1 can induce apoptosis by stimulating increase in concentrations of pro-apoptotic proteins such as BNIP3.

 However, during hypoxia, there is complex equilibrium between factors inducing or inhibiting apoptosis, or even stimulating cell proliferation thus, understanding these factors can help make appropriate selection of cancer therapeutic regimen, including adjuvant therapy (, Greijer & Van der Wall, 2004).  According to Majeed etal (2021), many ascorbic acid analogous or ligands have been

produced for their anti-cancer and anti-oxidant properties. According to Majeed etal (2021), in 2018, the World Health Organization (WHO) projects that 9.6 million people succumb to cancer and predicts even 16.4 million mortalities by 2040.

According to Majeed etal (2021), ascorbic acid health supplements are distributed in many different formulations that include powders for oral suspension, capsules, and granules for oral suspension,  powders for oral solution, tablets,  caplets, oral drops for pediatrics, and syrups in combination with proteins, omega-3 fatty  acids, sugar, water soluble and fat soluble vitamins, L-Arginine, and minerals.

Majeed etal (2021) recalls that depending on the route of administration, ascorbic acid induces either antioxidant, anticancer, or pro-oxidant activity; lower plasma concentration, antioxidant activity; at higher plasma concentration, anticancer activity; at higher pharmacological plasma concentrations, pro-oxidant activity. According to Cardona-Munoz etal (2020), pro-oxidants are compounds that elicit oxidative stress by elevating ROS production and decreasing antioxidant activity. N-Acetylcysteine protects against the development Parkinson Disease by maintaining appropriate levels of brain glutathione (Cardona-Munoz etal, 2020).

Elevated levels of ROS and RNS (reactive nitrogen species) can trigger cell injury especially, the mitochondrial pathway. Oxidative stress can induce apoptosis signaling in neurons. According to Huang etal (2013), TET family of proteins (enzymes/catalysts) converts 5-methylcystosine (5Mc) to 5-hydroxymethylcystosine (5hmC) that can further be oxidized and repaired by thymine DNA Glycosylase (TDG) to alter gene expression in embryonic and adult tissues.

DNA glycosylases are the first DNA repair enzymes mobilized for the repair of oxidative damage. Cardona-Munoz etal (2020) shows that ROS are relevant constituents of cellular homeostasis. However, excessive production of ROS can induce transcription errors that can trigger dysfunction in expression of different proteins.

 Ascorbic acid plays the role of volatile antioxidant by neutralizing free radicals of oxygen, nitrogen, and sulphur while enhancing the action of another antioxidant, vitamin E or tocopherol. Thus, ascorbic acid protects from DNA damage, amino acid metabolites, and lipids from oxidation triggered by free radicals hence, preventing disruptive mutations that usually result in cancer. Pharmacotherapeutically, ascorbic acid generates H2O2 in cancer cells through organometallic reaction thereby, eliciting selective cytotoxicity of cancer cells.

 Most of the poor prognoses of cancer illness are due to metastasis of the cancer cells to neighboring or adjacent organs through systemic circulation via blood and lymphatic vessels thus, cancer becomes incurable and deadly after spreading to distant organs. However, ascorbic acid at high plasma concentration controls cell migration and confines the tumor in situ (Cardona-Munoz etal, 2020). As a pro-oxidant, ascorbic inflicts damages to the cancerous through such mechanisms of action as oxidative stress, apoptosis etc.

METABOLISM OF ASCORBIC ACID

Ascorbic acid exists in L-Ascorbic Acid and L-DehydroAscorbic Acid moieties. Following oxidation, L-DehydroAscorbic Acid irreversibly yields 2,3-Diketo-L-Gulonic Acid that is converted to C5 Aldonic acids followed by D-Xylulose 5-P that later enters  into key metabolic process through the pentose phosphate pathway.  Also, 2,3-Diketo-L-Gulonic acid is converted to L-Erythrulose that is transformed to 3-Deoxythreosone.

Due to its intricate chemical structure, L-Dehydroascorbic acid can generate various products that can contribute to body pathophysiology, including 3-Deoxythreosone, an unstable agent that glycates lens proteins and oxalates that contribute to the development of nephrolithiasis by forming calcium oxalate or calculus. The metabolites of ascorbic acid are excreted in urine.

Meanwhile, it’s important to note the relevant role played by the sodium-dependent Vitamin C transporter (SVCT) in the transport of ascorbate, the active form of Vitamin C to the target site, by actively facilitating its permeability across the cell membrane, with the aid of the sodium gradient to catalyze the process. Nonetheless, in 1976, Ewan Cameron and Linus Pauling report that ascorbic acid administration to cancer patients improves their prognosis. Hence, ascorbic acid attracts significant interest for its potential to possess anticancer properties.

Several studies are conducted to evaluate the anticancer potential of ascorbic acid. Cancer cells have various means of growth and invasion that include HIF, TET, and GLUTs. HIF controls the expression of genes associated with angiogenesis, anti-apoptotic activity, stem cell regeneration, metastasis, and therapeutic outcome. TET proteins are associated with the induction of cancer stem   cells by changing the metabolic and epigenetic profiles of cells. GLUTs facilitate the delivery of glucose to cancer cells thereby, enhancing growth and proliferation (Majeed etal, 2021).

 According to Boss etal (2019), many cancer patients undergoing chemotherapy in intensive care experience ascorbic acid deficiency. Ascorbic acid induces the generation and mobilization of immune cells hence, supplementation can be used to boost immunity in those patients.  In addition, treatment with vitamin C has very high therapeutic window with minimized risk of toxicity (Boss etal, 2019). According to Bejjany etal (2018), colorectal cancer is one of the three most common types of cancer in men and the second most common in women. About one million people are diagnosed with colorectal cancer worldwide annually.

Bejjany etal (2018) stresses that ascorbic acid has shown tremendous effectiveness and potency on tumor response, improved prognosis, and better quality of  life. Bejjany etal (2018) study focuses on the three mechanisms of action of ascorbic acid in its efficacy in cancer treatment that include effect on glycolysis in tumors with mutation, high  plasma concentration requiring intravenous administration, and effect on  wide type RAS.

According to Bejjany etal (2018), while healthy cells extract energy from ATP, cancer cells use alternative process termed Warburg Effect or Aerobic Glycolysis to derive energy. This alternative process of extracting energy is a metabolic reversal whereby, glucose is absorbed faster in response to the excessive energy demand of the highly proliferating cancer cells, induced by over-expression of glucose transporter s or GLUTs.

 Recent studies on colon cancer cells show that Wingless-related integration site (WnT) signaling is necessary for tissue development. When altered, it plays a significant role in Warburg Effect and angiogenesis as well. Study conducted by Pate etal about the effect of inhibiting Warburg Effect signaling on colon cancer cells.  The studies show decrease in lactate generation, increase in ATP generation through oxidative phosphorylation and reduced glucose absorption thereby, disrupting the WARBURG EFFECT alternative metabolic pathway.

According to Aguilera etal (2016), KRAS mutation is often involved in many unresponsive tumors with very poor prognosis such as colon and pancreatic cancer. This is due to serious alterations in normal cell metabolism and clinical resistance chemotherapy. However, in1931, Otto Warburg states that cancer is primarily caused by altered metabolic pathways involved in energy extraction, later known as WARBURG EFFECT. Ascorbic acid has shown to disrupt Warburg Effect by the resultant reduction in GLUT-1, glucose transporter expression. KRAS disrupts the alternative metabolic pathway through which energy is extracted from glucose. Research by Xu Yun etal has shown that oxidized vitamin C or pro-oxidant has anti-cancer effect.  It neutralizes CRC cells depending on KRAS mutation status.

            Ascorbic acid selectively neutralizes mutant colon cancer cells alone or in adjuvant with Cetuximab.  It should be re4called that RAS proteins regulate signaling pathways necessary for cell prolife4rationand differentiation. Research results show that vitamin C is able to induce RAS disruption from cell plasma membrane thus, vitamin C penetrates through cancer cells, scavenging over reactive oxygen species or ROS thereby, inducing RAS detachment from plasma membrane. Consequently, phosphorylation pathway is aborted. The result is the anticancer effect of vitamin C (Aguilera etal, 2016).  According to Maekawa etal (2022), ascorbic acid has various effects that contribute to its complexity of actions.  When administered orally, ascorbic acid has very low plasma concentrations thus, acts as co-factor for anti-oxidant effects, collagen secretion, and HIF-alpha catabolism.

             However, when administered intravenously, large plasmas concentration is achieved, resulting in pro-oxidative-inducing activity with anticancer effects through reactive oxygen species (ROS). Thus, intravenous administration of ascorbic acid at high plasma concentrations is necessary to the appropriate therapeutic effects on cancer cells during ascorbic acid chemotherapy.  According to Dellaire etal (2021), cancer is triggered by intricate interplay of cumulative pathophysiological factors that include genetic, behavioral, metabolic, and contextual combination that leads to alterations that over time result in neoplasm.

 In terms of cancer prevention and intervention approaches that complement the main course of chemotherapy, such as lifestyle adjustment quitting smoking, maintaining healthy weight limiting dietary fats and food additives especially, those implicated as carcinogenic, including anticancer phytochemicals from plants and supplements in daily ration. According to Gegotec& Skrzydlewska (2022), ascorbic acid occurs endogenously as ascorbate and also available exogenously as ascorbic acid analogues and ligands.  It’s isolated  for  the  first  time  by  a  Hungarian  biochemist  named  Albert Szent-Gyorgyi. The name ascorbic acid is derived from scorbutus, meaning scurvy, the gum disease associated with ascorbic acid deficiency (Gęgotek & Skrzydlewska, 2022).

Ascorbic acid is an organic compound belonging to the family of unsaturated polyhydroxy alcohols, a water soluble ketolactone with six carbon atoms, eight hydrogen atoms and six oxygen atoms (C6H8O6).  According to Ge etal (2021), vitamin C exposes renal cell carcinoma to anti-PD-L1therapy. In other words, the combination of Vitamin C and anti-PD-L1 proves to be inhibitory against the proliferation of cancerous renal cells (renal carcinoma). This is another beneficial instance of adjuvant and complementary chemotherapy over monotherapy (Gęgotek & Skrzydlewska, 2022).

INHIBITING GLYCOLYSIS IN CANCER CELLS AND ITS EFFECTS

According to Majeed etal (2021), in early Otto Warburg and his colleagues discover that an increased amount of glucose is consumed for glycolysis by tumor cells in absence surplus oxygen. This is later known as the WARBURG EFFECT. It’s an important physiological process for tumor perfusion and proliferation under hypoxic condition. This alteration in glycolytic metabolic pathway enables adequate or even excessive perfusion and rapid glycolysis higher than in healthy cells.

Mutations of KRAS and BRAS genes in cancer cells upgrade GLUT-1 that can be targeted for cancer treatment. It’s assumed that Vitamin C in high concentration can selectively disrupt the mutated KRAS and BRAS. The therapeutic modulation of GLUT-1 regulation and its glucose supply pathway can be applied in depriving cancer cells of much needed constant supply of energy through the altered metabolic pathway and the alternative source of glycolysis thereby, limiting energy supply below the threshold necessary to induce WARBURG EFFECT. In other words, restricting much needed perfusion to the cancer cells is the goal. This can elicit hypoxia and apoptosis.

According to Majeed etal (2021), in gastric and renal cancer, there is increased expression of GLUT-1 that catalyzes rapid glycolysis and high doses of ascorbic acid treatment have shown to be effective in selectively disrupting over-expression of GLUT-1. Thus, ascorbic acid can induce cytotoxicity in cancer cells by disrupting glucose metabolism. Following the administration of ascorbic acid into the body, it is oxidized to Dehydroascorbate (DHA). Due to its molecular similarity to glucose, DHA is uptaken by KRAS or BRAS mutated GLUT-1 in a tumor. Once accessing the cell, DHA in the presence of nicotinamide adenine Dinucleotide Phosphate (NADPH) and Glutathione (GSH) is converted back to ascorbic acid.

 In the process of converting back to ascorbic acid, there is change in GSH and NADPH to Glutathione Disulphide (GSSG) and oxidized nicotinamide adenine Dinucleotide Phosphate (NADP+), respectively produces cellular ROS. Excess cellular ROS can damage the DNA. Damage to the DNA can lead to transcription errors, potential mutations, can result in cancer over time. Thus, I think cancer chemotherapy with ascorbic acid should account for DNA damage and potential repair agents.

EXCERPT TWO:

According to a research study, breast cancer resistant protein or Bcrp plays a critical role in limiting the permeability of xenobiotic compounds, including drugs across the blood brain barrier and the blood testes barrier. However, the effect of the functional limitation of breast cancer resistance protein is also regulated by P-glycoprotein activity. Therefore, the potential interpretation for differences in the effect of Bcrp on the in-situ uptake of drugs and the distribution of drugs across the blood-brain barrier at steady state or Tissue/plasma concentration ratio (Kp value) is probably due to the impact of P-glycoprotein activity in regulating the limiting functional effect of Bcrp as selective permeability of xenobiotic compound gatekeeper.

 Nonetheless, the effect of Bcrp on the in-situ uptake of drugs is weaker than on the permeability of drugs across the blood-brain barrier at steady Kp value because of the regulatory effect of P-glycoprotein on Bcrp.

In the last sentence of the abstract, the authors postulate that the in vivo significance of Bcrp is modulated by P-glycoprotein activity. This declaration means that while Bcrp of special interest in this study, including potential new drug agonist targeting, the impact of P-glycoprotein as a potential antagonist or partial agonist is of considerable importance too. The experiment can include further exploring P-glycoprotein as an antagonist or partial agonist to Bcrp agonist.

Finally, the usual chemotherapy for cancer involves the main therapy course and supportive or adjunct therapy. As we have seen in the Folate-PEGylated LA-Niosomes with the combination of both Letrozole and Ascorbic Acid (Akbar etal, 2022). In pharmacokinetics, it’s one thing to administer drug therapy, it’s another task ensuring bioavailability. Potential problems associated with inhibitors of efflux transporters such as the regulatory impact of P-glycoprotein on the Bcrp is that the effect can either be potentiating or delimiting. In this case, P-glycoprotein can serve as antagonist or partial agonist that mediates the desired effect of Bcrp in cancer chemotherapy.

 Similarly, in Folate-PEGylated LA-niosomes, bioavailability of the adjunct therapies of Letrozole and Ascorbic Acid combination at the target cancer cells is enhanced by nanocarriers or nanoparticles for optimum efficacy (Akbar etal, 2022). According to Akbar etal (2022), fighting cancer demands the delivery of various therapeutics to the target carcinogenic cells by taking advantage of the synergistic effects of complementary medicine.

In their research study, the authors present a Folate-PEGylated Niosomes as an efficient nanocarrier for targeted simultaneous delivery of hydrophobic and hydrophilic letrozole and ascorbic acid to breast cancer cells. The formulation of the noisome nanocarrier is amplified by altering the proportion of cholesterol and emulsifiers to optimize the drug loading, bringing the volume of the nanocarriers to minimum. The peak drug carriers are further programmed with Folate-PEGylated molecules to facilitate the efficiency of drug delivery to the breast cancer cells thus, eschews scavenging by macrophages (Akbar etal, 2022).

EXCERPT THREE:

OTHER NON-TOXIC APPROACHES TO CANCER THERAPY

Meanwhile, one of the characteristics that separate anticancer agents from other drugs is the frequency of sides effects at therapeutic doses. The frequency and severity of side effects of anticancer drugs at therapeutic level can be as a result of compromised physiological constituents of the patient. The body is not adequately metabolizing and absorbing nutrients as in non-cancer disease treatment. The cells are being deprived of the energy needed to function effectively. Thus, the anticancer drugs become more toxic in a compromised body system of the cancer patient than usual. I used to mistakenly allude alopecia in cancer patients to the manifestation of the cancer itself. However, hair loss is as a result of aggressive cancer chemotherapy.  

The etiology and pathophysiological manifestations of cancer are important lecture topics because cancer is among the leading causes of death in US. Cancer cells are highly proliferating cells that require constant and excessive supply of nutrients and blood to sustain the cells. Therefore, restricting nutrient and blood supply can help confine the tumor in situ. It’s worth recalling that angiogenesis in cancer tumor is an attempt to generate new blood vessels to sustain the tumor’s unquenchable thirst for nutrients and blood. Thus, targeting perfusion is commensurate to targeting angiogenesis as well in conventional cancer pharmacotherapy.

However, in ideal world, there are other non-toxic approaches to cancer therapy such as detoxification paired with appropriate nutrients that also target perfusion.  One serious problem with cancer pharmacotherapy is that most therapies are very harsh to normal cells but most of the time fails to have any significant therapeutic effects on the targeted cancer cells. The discovery of nanoparticles can also help to deliver cancer drugs to its exact target organs or cells. Cancer pharmacotherapy is also broad-spectrum in action. In other words, it seldom distinguishes between cancer cells and normal healthy cells that should otherwise be spared. I used to wonder whether alopecia or hair loss experienced by cancer patients is one of the pathophysiological manifestations of cancer.

 However, hair loss is the undesirable impact of aggressive cancer drugs. There is similar serious impact on reproduction. Therefore, using less aggressive, non-toxic treatment approaches to cancer such as detoxification and organic nutrients can not only improve survival rates but can restore health as well. There are effective non-toxic OTC drugs that are not considered belonging to the mainstream conventional cancer treatment.

CONCLUSION

Linus Pauling and Ewan Cameron are among the pioneers of research studies about the anticancer potential of ascorbic acid or vitamin C. In 1976, Ewan and Cameron report that ascorbic acid administration to cancer patients improves their prognosis. Henceforth, ascorbic acid attracts significant research interests for its anticancer properties. In early 20th century, Otto Warburg hypothesizes that cancer involves alterations in glycolytic metabolic pathway that provide alternative shift from energy supply to cells through glycolysis.

 Normal cells extract energy as ATP through glycolysis, whereas the rapidly proliferating cancer cells, with the increased demand for perfusion extract energy through alternative glycolytic pathway facilitated by over-expression of the glucose transporters (GLUTs-1) otherwise, known as the WARBURG EFFECT.

The mechanisms of action of ascorbic acid include anticancer effects, antioxidant effects, and pro-oxidant effects expressed through HIF, TET, and GLUT-1.  Among the chemotherapeutic targets using ascorbic acid, disrupting the alternative glycolytic pathway that supplies energy to the cancer cells, including controlling over-expression of GLUT-1 can be effective.

Also, considering that the metabolism of ascorbic involves the release of reactive oxygen species (ROS) that induce oxidative stress, which can damage the DNA; including drugs with DNA repair potentials can minimize the risks of further mutations. Also, complementary and adjuvant chemotherapy with ascorbic acid have shown to be effective as well, according to research studies. For maximum therapeutic benefits in cancer treatment, intravenous administration of ascorbic acid is recommended, from research studies.

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