High-dose parenteral ascorbate (vitamin C) enhances ovarian cancer chemosensitivity in vivo.

  • Major finding: High-dose parenteral ascorbate (vitamin C) enhances ovarian cancer chemosensitivity in vivo.

  • Clinical relevance: Intravenous ascorbate reduces carboplatin and paclitaxel toxicity in patients with ovarian cancer.

  • Impact: High-dose intravenous ascorbate may be a beneficial adjuvant to conventional ovarian cancer chemotherapy.

Clinical studies have not demonstrated a benefit for oral ascorbate (vitamin C) in cancer treatment. However, much higher plasma concentrations of ascorbate can safely be achieved through intravenous infusion, and recent studies have shown that pharmacologic concentrations of ascorbate lead to the formation of ascorbate radicals and peroxide that are selectively cytotoxic to cancer cells. Ma and colleagues investigated ascorbate-induced cytotoxicity in ovarian cancer and found that several ovarian cancer cell lines were sensitive to millimolar concentrations of ascorbate in vitro, whereas nontumorigenic ovarian epithelial cells were not. Killing of cancer cells depended upon ascorbate-mediated peroxide production, which led to depletion of cellular ATP levels and induction of DNA double-strand breaks that activated ataxia telangiectasia mutated (ATM) and adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR expression and phosphorylation in vitro and in athymic mice implanted with ovarian cancer cells. Interestingly, ascorbate strongly enhanced in vitro killing of ovarian cancer cells by the first-line chemotherapy agent carboplatin, and intraperitoneally administered ascorbate synergized with both carboplatin and paclitaxel (singly or in combination) to reduce tumor burden in tumor-implanted mice. Because neither toxicity nor organ pathology was observed in ascorbate-treated mice, the authors initiated a pilot phase I/IIa clinical trial to evaluate the safety of ascorbate combination therapy in patients with stage III or IV ovarian cancer. Twelve patients received standard carboplatin–paclitaxel combination therapy for 6 months, and 13 patients additionally received ascorbate infusions for 12 months. Notably, patients receiving ascorbate experienced a lower incidence of grade 1 and 2 toxicities and had reduced toxicities in most categories compared with those who did not receive ascorbate. Although this study was not powered to test efficacy, the addition of ascorbate to chemotherapy showed a trend toward improved survival and delayed disease progression, suggesting that larger clinical trials of high-dose ascorbate adjuvant therapy are warranted.

Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 2014;6:222ra18.