Treatment of Prostate Cancer Using Deimination Antagonists and Microvesicle Technology.

Abstract

Cellular microvesicle (MV) release, which occurs in most eukaryotic cells, is also involved in cancer progression and has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination in the mechanism of MV biogenesis. Elevated PAD expression observed in cancers may contribute to increased MV shedding from cancer cells and contribute to cancer progression. The use of pan-PAD inhibitor Cl-Amidine (Cl-Am) showed that, following the pharmacological inhibition of PAD-mediated deimination, cellular MV release was significantly reduced, rendering prostate cancer cells significantly more susceptible to chemotherapeutic drugs. Combined Cl-Am and methotrexate (MTX) treatment of prostate cancer cells increased the cytotoxic effect of MTX. Refined PAD inhibitors that selectively manipulate MV biogenesis may form part of novel combination therapies in cancer treatment.