High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study

Abstract

Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate’s anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

Pharmacological ascorbate induces ‘BRCAness’ and enhances the effects of Poly(ADP‑Ribose) polymerase inhibitors against BRCA1/2 wild‑type ovarian cancer

“…Such a strategy could be applied to a variety of heterogeneous and hard-to-treat malignancies, including breast, pancreatic and prostate cancer, where BRCA1, BRCA2 or other HR repair proteins are instrumental in the repair of DNA DSBs and the potential of PARPis has not yet been fully exploited (39). Consistent with previous studies (22,29,40), the data in the present study demonstrated that treatment with pharmacological ascorbate resulted in the production of H 2 O 2 , which damages DNA, leading to PARP activation, and this was impaired by the PARPis. The oxidative stress induced by pharmacological ascorbate caused excessive DNA DSBs in BRCA1/2 wild-type EOC cells within the first 6 h of treatment.…”

“…It is well-documented that high-dose IVC is well tolerated with minimal toxicity in humans (26)(27)(28)47). A previous Phase I/IIa clinical trials in patients with EOC (20) and pancreatic cancer (40), together with other trials (25,27,28), have consistently demonstrated that adding IVC to standard treatments (chemotherapy or radiation therapy) is safe, well tolerated, feasible and potentially effective. Addition of IVC to carboplatin and paclitaxel chemotherapy substantially decreased side-effects in patients with stage III or IV EOC (20).…”

Enhancing the Effect of Pharmacological Ascorbate in Cancer Therapy via Acid‐Triggered Ferritin Nanoparticles

“…Surprisingly, intravenous pharmacological ascorbate is now in wide use by the American public . Extensive literatures and clinical trials revealed that pharmacological ascorbate could be a promising chemotherapeutic drug for cancer patients . Recent clinical trials also showed that it is a potential adjuvant to improve the efficacy of standard cancer therapy in ovarian, brain cancer, and lung cancer patients .…”

Therapeutic Use of Vitamin C in Cancer: Physiological Considerations

“…On the other hand, a study analyzing 13 glioblastoma patients receiving radiotherapy and 14 non-smallcell lung cancer patients receiving chemotherapy, showed that IV ascorbate treatment extended survival of patients (Schoenfeld et al, 2017). Similarly, a report analyzing 14 pancreatic cancer patients receiving IV ascorbate and chemotherapy showed the possibility to prolong survival of patients (Polireddy et al, 2017). Another report performed in 73 patients with acute myeloid leukemia showed that IV ascorbate treatment combined with chemotherapy produced a higher complete remission and prolonged survival compared to patients who received only chemotherapy (Zhao et al, 2018).…”