Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells

BACKGROUND: Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. However, almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. Thus, new chemotherapeutic agents that can overcome the CDDP-resistant cancer cells will improve the survival of advanced cancer patients. METHODS: We synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl(2) (L)] and [PdCl(2) (L)]. CDDP-resistant gastric cancer cell lines were established by continuous exposure to CDDP, and gene expression in the CDDP-resistant gastric cancer cells was analyzed. The cytotoxicity and apoptosis induced by [PtCl(2) (L)] and [PdCl(2) (L)] in CDDP-sensitive and CDDP-resistant gastric cancer cells were evaluated. DNA double-strand breaks by drugs were assessed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established and antitumor effects were also examined in vivo. RESULTS: CDDP-resistant gastric cancer cells exhibit ABCB1 and CDKN2A gene up-regulation, as compared with CDDP-sensitive gastric cancer cells. In the analyses of CDDP-resistant gastric cancer cells, [PdCl(2) (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl(2) (L)] induced DNA double-strand breaks. CONCLUSION: These results indicate that [PdCl(2) (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications.