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Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma
Francois Lamoureux1, Marc Baud'huin2, Benjamin Ory1
1Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes F-44035, France. INSERM, UMR 957, Nantes F-44035, France. LUNAM Université. Equipe labellisée LIGUE 2012, Nantes, cedex.
Purpose:
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.
Methods:
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).
Results:
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.
Conclusion:
These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma.
Insights
Targeting clusterin (CLU) with OGX-011 enhances zoledronic acid (ZOL) chemotherapy in osteosarcoma. This combination therapy reduces tumor growth and improves survival by suppressing ZOL-induced CLU, a protein linked to treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma treatment faces challenges with chemotherapy response, necessitating novel therapeutic strategies to improve patient survival.
- Zoledronic acid (ZOL) is a potential adjuvant therapy for osteosarcoma, aiming to mitigate the osteolytic bone tumor component.
- ZOL can increase heat shock proteins (Hsp), including clusterin (CLU), potentially promoting tumor cell survival and resistance.
Purpose of the Study:
- To investigate the hypothesis that targeting CLU with OGX-011 can suppress ZOL-induced CLU production.
- To evaluate if OGX-011 enhances ZOL-induced cell death in osteosarcoma (OS) cells.
- To assess the combined effects of OGX-011 and ZOL on OS cell growth, viability, apoptosis, and cell cycle.
Main Methods:
- In vitro studies on ZOL-sensitive and -resistant human OS cell lines (SaOS2, U2OS, MG63, MNNG/HOS).
- Assessed cell growth, viability, apoptosis, and cell cycle repartition.
- In vivo studies using MNNG/HOS xenograft models to evaluate tumor growth inhibition and survival.
Main Results:
- ZOL increased HSPs, particularly CLU, in a dose- and time-dependent manner, linked to increased HSF1 transcription activity.
- Higher CLU expression was observed in ZOL-resistant OS cells; CLU overexpression protected sensitive cells from ZOL-induced death.
- OGX-011 suppressed ZOL-induced CLU increases, synergistically enhanced ZOL's effects on cell growth and apoptosis, and decreased HSPs, MDR1, and HSF1 activity.
- In vivo, OGX-011 potentiated ZOL's effect, significantly inhibiting tumor growth by 50% and prolonging survival.
Conclusions:
- ZOL-mediated CLU induction in osteosarcoma can be attenuated by OGX-011.
- The combination of OGX-011 and ZOL demonstrates synergistic effects in delaying osteosarcoma progression.
- Targeting CLU represents a promising strategy to enhance chemotherapy efficacy in osteosarcoma treatment.
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