Enhancement of Cisplatin Sensitivity in Lung Cancer Xenografts by Liposome-Mediated Delivery of the Plasmid Expressing Small Hairpin RNA Targeting Survivin

Abstract

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is abundantly expressed in a variety of cancer cells, including lung cancer cells, resulting in low sensitivity of these cells to various apoptotic stimuli; Cisplatin (CDDP), a commonly used chemotherapeutic agent of several cancers, has a major limitation because of its toxicity at high concentration. In the present study, we constructed a plasmid encoding Survivin shRNA to knockdown survivin with low dose DDP both in vitro and in vivo. The specificity and potency of the shRNA were validated by western blot, flow cytometric and MTT in H292 lung cancers cells. In vivo, therapy experiments were conducted on nude mice bearing H292 xenograft tumors. The Survivin shRNA expression plasmid was administered systemically in combination with low-dose CDDP on a frequent basis. Assessments of angiogenesis, cell proliferation and apoptosis were performed by using immunohistochemistry against CD31, Ki67 and TUNEL assays, respectively. The results revealed that treatment with the Survivin shRNA plus low-dose CDDP reduced volume by approximately 83.13% compared with the blank control (P < 0.01), accompanied with angiogenesis inhibition (p < 0.01), tumor cell proliferation suppression (p < 0.05) and apoptosis induction (p < 0.01). Moreover, combination treatment also significantly reduced the mean tumor volume compared with other treatment alone (p < 0.05). Taken together, our study suggested that silencing of survivin sensitized H292 lung cancer cells to chemotherapy of CDDP, suggesting potential applications of the combined approach in the treatment of lung cancer.