Abstract
BackgroundCisplatin (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.MethodsWe synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl2 (L)] and [PdCl2 (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 [PtCl2 (L)] and [PdCl2 (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.ResultsCDDP-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, [PdCl2 (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl2 (L)] induced DNA double-strand breaks.ConclusionThese results indicate that [PdCl2 (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications.
Highlights
Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer
[PdCl2 (L)] induced apoptosis in CDDP-resistant gastric cancer cell lines We examined apoptosis induction by CDDP, [PtCl2 (L)], [PdCl2 (L)], L-OHP and CABDA in the gastric cancer cell lines MKN45 (0) and MKN45 (CDDP) (Figure 2A)
In the CDDPresistant subline (MKN45 (CDDP)), γ-H2AX protein levels increased with [PdCl2 (L)], but did not increase with CDDP (Figure 2B). These results indicated that [PdCl2 (L)], but not CDDP induced DNA double-strand breaks in CDDP-resistant gastric cancer cells
Summary
Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. Almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. New chemotherapeutic agents that can overcome the CDDP-resistant cancer cells will improve the survival of advanced cancer patients. Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer and is used in combination regimens. CDDP-based combination chemotherapy regimens have several disadvantages, including side effects such as nephrotoxicity, neurotoxicity, ototoxicity and vomiting. Several mechanisms are involved in CDDP resistance [5] Such mechanisms include decreased intracellular drug accumulation and/or increased drug efflux [6,7,8,9], drug inactivation by increased levels of cellular thiols [6,10], increased nucleotide excision-repair activity [9,11] and evasion of apoptosis [6,12]. For continued progress in cancer therapy, more effective drugs must be found
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