**6. Ascorbic acid and cancer**

Cancer is a broad term that describes the disease that results when cellular changes cause the uncontrolled growth and division of cells [52]. Presently, cancer has been identified as a complicated disorder that involves the modification of gene articulation, supports cell survival and acceleration, and can be altered by genomic and epigenomic components [53]. Genomic components are defined by the modifications at the sites of the genes, aiding mutations, while epigenomic components adapt to changes that do not reverse the chain of DNA bases except their form by histone modification, methylations in DNA bases, and nucleosome alteration [54, 55].

Cancer cells function within an advanced level of oxidative stress, as a result of elevated standard degree of ROS, oncogenic alteration, and metabolic deterioration [56].

Redox imbalance induces cell damage caused by lipid peroxidation generating derangement and loss of function and integrity of the cell membrane, as well as DNA damage, promoting genomic instability and cell proliferation, thereby increasing the somatic mutations and neoplastic transformation [57]. It is estimated that in 2030, the global burden of cancer will be 21.4 million new cases and 13.2 million deaths, mainly due to the growth and aging of the population [58]. The World Health Organization (WHO) states that the consumption of fruits and vegetables can help prevent cancer due to their composition with nutrients such as vitamins, minerals, and fiber [59]. As published in the Dietary Reference Intake (DRI), food containing antioxidants such as ascorbic acid, carotenoids, tocopherol, selenium, and flavonoids are suggested to be consumed because of their antagonistic reaction, as they often have the potential for cancer prevention, suppress degeneration of molecules, and formation of free radicals [60].

The relationship between vitamin C and cancer is still under study and is associated with antioxidant, prooxidant, and gene expression regulator properties [61]. The role of ascorbic acid on tumor advancement relays on whether it is administered orally or intravenously, together with the manifestation and the category of ascorbic acid transporters in the tumor cells. It has been reported that some cancer cells manifest an elevation in the expression of sodium vitamin C transporter 2 (SVCT2) and/or glucose transporter 1 (GLUT1) and absorbs more vitamin C than normal cells for the ascorbic acid transporter's expression [61]. The high expression of GLUT1 in tumors constitutes the principle of oncological diagnosis based on the positron emission tomography of 18F-fluorodeoxyglucose.

In treatment, ascorbic acid was selectively toxic to cancer cells in vitro and in vivo [62, 63]. In animal models, ascorbic acid either has anti-cancer activity similar to conventional chemotherapy or synergizes with it [64, 65]. Contrarily, there are no data showing that treatment of cancer with ascorbic acid interferes with chemotherapy. Early-phase clinical trials show that i.v. ascorbic acid at 1 g/kg over 90–120 minutes, two to three times weekly is well tolerated and may enhance chemo sensitivity as well as decrease chemotherapy-related side effects [66–68]. Agathocleous *et al*. [50] indicated the role of oral ascorbic acid in delaying cancer development in mice which was based on ascorbate-dependent activation of TET and HIF-PHD enzymes. In these mice, oral vitamin C postponed progression of genetically susceptible transplanted hematopoietic cells to acute myelogenous leukemia. In a similar study in lymphoma xenograft mode, tumor development was decreased by oral vitamin C, which had HIF-1-dependent anti tumorigenic properties [69]. Treatment of cancer to reduce tumor growth in many rodent models was mediated by parenteral ascorbic acid to produce treatment concentrations [62, 65, 70–72].

Ascorbic acid concentrations in cancer patients are often at deficiency concentrations [73, 74], the basis for which is still unknown. The justification for the above may include generalized cancer wasting, improved consumption of vitamins by cancer cells, or suppression of vitamin C carriers. It is consequently, in accordance to determine whether there is a place for vitamin C as a treatment regimen through rectification of vitamin C deficiency, irrespective of parenteral administration. The outcome of sporadic treatment trials in persons with advanced stages of cancers particularly colon and rectal cancers were negative [75]. Based on recent in vitro evidence, correction of ascorbate deficiency may aid conventional hypomethylating agents, that is, DNA methyltransferase inhibitors, to exert maximal effect [74]. The rationale for the use of high-dose i.v. ascorbate in cancer treatment is not to correct plasma deficiency, but rather to induce an oxidative stress on cancer cells [62] and to ensure adequate delivery of ascorbic acid within tumors for optimal cofactor function [76]. It is therefore important to accept that only parenteral ascorbic acid has yielded results for treatment success in the early phase of human trials in the literature. The use of rodent models in confirmed cancer cases, only parenteral ascorbic acid has proven to be beneficial irrespective of the model. This information gives directions for clinical trials [77].
