L-Canavanine Potentiates Cytotoxicity of Chemotherapeutic Drugs in Human Breast Cancer Cells

Background: Due to the high level of argininosuccinate synthase (ASS), a key enzyme for the formation of arginine from citrulline, human breast cancers are often resistant to arginine deprivation therapy. An antimetabolite, Lcanavanine (L-CAV), can be incorporated into proteins in the place of arginine, disturbing protein conformation and leading to cellular death. Objectives: This study was designed to investigate the potential of L-CAV to enhance the toxicity of chemotherapeutic drugs in the human breast cancer cell line MCF-7, and determine the most favorable drug combination to exert synergistic interaction in the presence or absence of arginine in the medium. Methods: Combination experiment based on the median-effect principle and mass-action law was conducted using constant ratios of cytotoxic agents as developed by Chou (2006). Results: We observed that L-CAV enhanced the toxicity of cisplatin (CIS) and vinblastine (VIN) in MCF-7, even in the presence of L-ARG. On the other hand, L-CAV potentiated the toxicity of doxorubicin (DOX), paclitaxel (PTX), 5- fluoruracil (5-FU), and amphotericin-B (AMP-B) in cells grown in arginine deprived media. Conclusion: We conclude that the combination of L-CAV with CIS or VIN can potentiate the toxicity for breast cancer cells. Thus this report presents a new possibility for treating human breast cancers known to be resistant to arginine deprivation. This initial study requires further investigation in in vivo experiments and exploration of the molecular mechanism of cellular response in human breast cancer.