Novel inhibitors of disulfide/methyl-ATP pump inhibit the proliferation of cancer cells: Analogs of methionine

Target-based chemotherapies have rapidly become a conventional approach to cancer treatment. However, cell membranes can be impermeable to some treatment candidates that require cellular internalization. Our previous in vitro study described several critical findings on the utility of L-methionine in cancer chemotherapy. First, over a range of 1-5 mg/L, L-methionine inhibited cancer cell growth and proliferation. Second, p53 upregulation and its post-translational modification occurred via ubiquitylation. Third, L-methionine suppressed cell cycle progression in HPAC pancreatic, LNCaP prostate, and MCF-7 breast cancer cells but not in their corresponding benign cells. Finally, L-methionine induced standard changes to the molecular signatures of cancer cells. Previous studies of methionine analogs have implicated their therapeutic potential for multiple malignancies. However, the sulfur and methyl underlying countercurrent exchange mechanisms and electrical-chemical gradients have not been defined clearly. Based on the results obtained in our previous work with cancer cells, we hypothesize the existence of a novel disulfide/methyl-ATP pump in the membrane of cancer cells involved in mediating L-methionine uptake. The cellular entry of methionine is mediated via a sulfur atom and methyl donors from L-methionine replacing the oxygen, similar to the sulfur exchange mechanisms of cellular invasion by alcohol or diphtheria toxin. Methionine analogs can compete for or inhibit the cancer cell membrane disulfide/ methyl-ATP pump, possibly inhibiting these cell's import mechanisms. ATP pumps systematically help re-establish sulfur and methyl levels in the cell via a countercurrent exchange mechanism and trigger an orchestrated activation of p53 protein, culminating in cell cycle control and reduced cell proliferation. Targeting this potentially novel disulfide/methyl-ATP pump could be an effective chemotherapeutic treatment for various cancer types. Thus, further mechanistic studies are warranted.