Synergistic interaction between platinum-based antitumor agents and demethylcantharidin

Abstract 

A novel series of TCM-platinum complexes [Pt(C₈H₈O₅)(NH₂R)₂] 1–5, designed from incorporating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety was found to circumvent cisplatin resistance in mouse leukemia and human hepatocellular carcinoma. These properties are most likely due to the inclusion of the protein phosphatase 2A (PP2A)-inhibiting demethylcantharidin in the novel compounds. We have investigated the potential synergistic effect of combining demethylcantharidin with a platinum-based antitumor agent, such as cisplatin, carboplatin, or oxaliplatin in vitro against L1210 mouse leukemia and SK-Hep-1 human hepatocellular carcinoma, and in vivo against a SK-Hep-1 subcutaneous-inoculated xenograft in nude mice, using median effect analysis. Demethylcantharidin and the platinum antitumor agents were synergistic in all cell lines tested in vitro, and the most effective antiproliferative regimen was when demethylcantharidin was added 24h before cisplatin. Synergistic antitumor activity was also demonstrated in vivo without undue toxicity; no excessive loss in mouse body weight or overt pathology were observed at the effective doses. The results support a new approach for augmenting cytotoxic effect of established Pt-based drugs with demethylcantharidin in treating human hepatocellular carcinoma and other solid tumors.

Keywords: Synergy, Cytotoxicity, Platinum antitumor agents, Protein phosphatase inhibitors, Demethylcantharidin

Abbreviations: DMC, demethylcantharidin, PP2A, protein phosphatase 2A, NER, nucleotide excision repair, TCM, traditional Chinese medicine, HCC, hepatocellular carcinoma, CI, combination index, CR, combination ratio, s.c., subcutaneous