Differential Dose Dependent Effects of Ascorbate on Cancer Cell Toxicity or Proliferation by Ascorbate; Regulation of Matrix metalloproteinases and Transforming Growth Factor‐beta.

Vitamin C (ascorbate) regulates the extracellular matrix (ECM) that is remodeled by the matrix metalloproteinases (MMPs) for cancer metastasis. An endogenous regulator of cell growth and the ECM is transforming growth factor–beta (TGF‐β). The potential of ascorbate as an anticancer agent was examined with regards to cell viability and the expression of MMPs and TGF‐β in three prevalent cancer cell lines – renal adenocarcinoma, melanoma and mammary cancer. Ascorbate significantly inhibited cancer cell viability at the lower concentrations and dramatically stimulated cell proliferation at the higher concentrations in all three cancer cell lines. The expression of MMPs and TGF‐β was drastically stimulated at the growth inhibitory ascorbate concentrations and inhibited at the growth stimulatory concentrations with correction for cell number. These effects were less drastic in total, without normalization for cell number, though similar with significant stimulation at the growth inhibitory concentrations in renal and mammary cancer cells and largely without effect at the growth stimulatory concentrations. The results indicate that the lower doses of ascorbate are toxic to cancer cells and the extracellular milieu, whereas the higher ascorbate concentrations give the cancer cells a metabolic/ proliferative advantage with minimal or beneficial extracellular matrix alterations. We are examining the potential of a vitamin E or a fern extract (Polypodium leucotomos) with anti‐carcinogenic properties to facilitiate the growth inhibitory property of ascorbate without damage to the extracellular matrix.