Abstract
BackgroundA high concentration of cisplatin (CDDP) induces apoptosis in many tumor cell lines. CDDP has been administered by infusion to avoid severe toxicity. Recently, it has been reported that changes in survivin expression or function may lead to tumor sensitization to chemical and physical agents. The aim of this study was to determine whether a dominant-negative mouse survivin mutant could enhance the anti-tumor activity of CDDP.MethodsA plasmid encoding the phosphorylation-defective dominant-negative mouse survivin threonine 34→alanine mutant (survivin T34A) complexed to a DOTAP-chol liposome (Lip-mS) was administered with or without CDDP in Lewis Lung Carcinoma (LLC) cells and in mice bearing LLC tumors, and the effects on apoptosis, tumor growth and angiogenesis were assessed. Data were analyzed using one-way analysis of variance(ANOVA), and a value of P < 0.05 was considered to be statistically significant.ResultsLLC cells treated with a combination of Lip-mS and CDDP displayed increased apoptosis compared with those treated with Lip-mS or CDDP alone. In mice bearing LLC tumors and treated with intravenous injections of Lip-mS and/or CDDP, combination treatment significantly reduced the mean tumor volume compared with either treatment alone. Moreover, the antitumor effect of Lip-mS combined with CDDP was greater than their anticipated additive effects.ConclusionThese data suggest that the dominant-negative survivin mutant, survivin T34A, sensitized LLC cells to chemotherapy of CDDP. The synergistic antitumor activity of the combination treatment may in part result from an increase in the apoptosis of tumor cells, inhibition of tumor angiogenesis and induction of a tumor-protective immune response.
Highlights
A high concentration of cisplatin (CDDP) induces apoptosis in many tumor cell lines
Previous studies have shown that reduction of survivin expression achieved by antisense strategies results in apoptotic cell death and sensitization to anticancer drugs in several tumor cell lines [26,27]. These results suggest that survivin expression is likely important for cell survival or resistance to chemotherapy in carcinomas
The survivin mutant had originally gained attention because it widely and promoted apoptosis and enhanced chemotherapy, and its function and mechanism have been studied in various tumor types [9,11,12,29]
Summary
A high concentration of cisplatin (CDDP) induces apoptosis in many tumor cell lines. CDDP has been administered by infusion to avoid severe toxicity. The aim of this study was to determine whether a dominant-negative mouse survivin mutant could enhance the anti-tumor activity of CDDP. It was reported that the survivin mutant Thr34TAla (survivin T34A) could abolish a phosphorylation site for cdc2cyclin B1 and prevent survivin binding to activated caspase-9[11]. This reduced tumor cell proliferative potential and led to caspase-dependent apoptosis in melanoma cell lines[9]. The present study was designed to determine whether Lip-mS could enhance the antitumor activity of CDDP chemotherapy and to explore the possible mechanisms of interaction between survivin targeting-agents and chemotherapy
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