Therapeutic potential of antisense (AS) Bcl-2 as a chemosensitizer for patients with gastric and breast carcinoma

摘要

BACKGROUND AND OBJECTIVE: Bcl-2 confers resistance to apoptosis resulting in reduction of the effectiveness of chemotherapy. We examined the effect of antisense (AS) Bcl-2 in combination with anticancer drug for targeting therapy against Bcl-2 in gastric and breast cancer cells. MATERIALS AND METHODS: One human gastric cancer cell line (MKN-45) and three breast cancer cell lines (BT-474, ZR-75-1 and MDA-MB-231) were examined. The effects of antisense Bcl-2 phosphorothioate oligonucleotides (AS ODNs: 18 mer) on chemosensitivity were tested in vitro and in vivo. Chemosensitivity was evaluated by the MTT assay, and the antitumor effect assessed in vivo by the success of xenograft transplantation into nude mice. RESULTS: Treatment with AS Bcl-2 ODNs resulted in sequence-specific reduction in protein expression, which was compared to controls. Treatment of MKN-45 cells with AS Bcl-2 increased sensitivity to adriamycin (ADM), cisplatin (CDDP), and paclitaxel (PTX) in vitro and in vivo. Similarly, treatment of BT-474, ZR-75-1, and MDA-MB-231 cells with AS Bcl-2 increased chemosensitivity to ADM, mitomycin C (MMC), PTX, and docetaxel (DOC). This occurred in the setting of increased Bax and cleaved poly (ADP-ribose) polymerase, as well as decreased Bcl-2 and pAkt. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, expression of CD80, CD83, CD86, and CD27, which was attenuated by methylation of the CpG-motifs of AS Bcl-2, suggesting the involvement of immunomodulatory effect of AS Bcl-2 through pDC and B cell although methylated CpG-failed to negate the increased antitumor effect of AS Bcl-2. CONCLUSION: Targeted therapy against Bcl-2 protein using AS ODNs might enhance the effects of chemotherapy in patients with gastric and breast cancer.