Abstract
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 (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL 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 CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells. The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS). In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50µg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone. These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma.
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumor in both children and young adults with a peak of incidence at 18 years [1, 2]
These results indicate that zoledronic acid (ZOL)-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma
First we assessed the effects of ZOL treatment on CLU expression in vivo in HOS-MNNG osteosarcoma xenografts using immunohistochemistry (Fig. 1A)
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumor in both children and young adults with a peak of incidence at 18 years [1, 2]. The tumor generally develops on the average part of the long bones (femur and tibia), at the vicinity of an articulation, mainly the knee or the shoulder. Current therapeutic protocols consist in neoadjuvant poly-chemotherapy associated with conservative surgery. The long-term survival rate is 60% to 75% at 5 years for patients with localized tumor but drastically goes down to 25% if pulmonary metastases are detected at diagnosis. Patients who do not respond to these conventional therapies have a poor prognosis. To significantly improve survival in children with OS, new therapeutic strategies targeting the molecular basis of OS and treatment resistance are required
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