Bone Abstracts

Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, zoledronic acid triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting clusterin (CLU) using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance zoledronic acid-induced cell death in osteosarcoma (OS) cells.

The combined effects of OGX-011 and zoledronic acid were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of zoledronic acid-sensitive or zoledronic acid-resistant human cell lines (SaOS2, U2OS, MG63 and HOS).

In OS cell lines, zoledronic acid increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF-1 transcription activity. The OS resistant cells to zoledronic acid exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to zoledronic acid-induced cell death by modulating the farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of zoledronic acid on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, Akt, and HSF-1 transcriptional activity. In vivo, OGX-011, administered three times a week (i.p., 20 mg/kg), potentiated the effect of zoledronic acid (s.c.; 100 mg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in HOS xenograft model compared to zoledronic acid alone.

These results indicate that zoledonic acid-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma.