G3139 antisense oligonucleotide directed against antiapoptotic Bcl‐2 enhances doxorubicin cytotoxicity in the FU‐SY‐1 synovial sarcoma cell line

Abstract

Synovial sarcoma (SS) is a highly aggressive, periarticular soft tissue sarcoma that causes death in more than half of affected children, adolescents, and young adults. Five- and 10-year survival rates are as low as 36 and 20%, respectively. Bcl-2, a negative regulator of apoptosis, is overexpressed in up to 90% of SS. Increased Bcl-2 expression not only leads to the development of cancer, but also to resistance of many anticancer chemotherapeutic agents. We hypothesized reducing Bcl-2 expression in SS should enhance doxorubicin cytotoxicity. Cell cultures representing two human sarcomas (FU-SY-1 SS and the pleomorphic SW982) and a primary human dermal fibroblast comparator (NHDF) were exposed in vitro to doxorubicin, or to doxorubicin preceded by Bcl-2 (G3139) antisense oligonucleotides, and assayed for cell survival, apoptosis, and modulations in Bcl-2 and Bcl-xL mRNA and protein content. SW982 sarcoma cells proved most susceptible to doxorubicin, while NHDF mesenchymal cells were least sensitive to doxorubicin. Treatment of FU-SY-1 SS with G3139 reduced Bcl-2 mRNA and protein levels, which enhanced doxorubicin-induced cell killing. There was a concurrent reduction in Bcl-xL mRNA following G3139 application in FU-SY-1 and NHDF cultures, but not in SW982. G3139 anti-Bcl-2 intervention sensitized the FU-SY-1 SS to doxorubicin, due to increased apoptosis. G3139 intervention was ineffective in the two non-SS cell lines.