Skip to Main content Skip to Navigation
Journal articles

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Abstract : PURPOSE: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma. EXPERIMENTAL DESIGN: The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14(+) monocytes. RESULTS: In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50 nmol/L) and induced apoptosis with an increase of sub-G1 fraction and cleaved PARP. These biologic events were accompanied by decreased expression of Akt, p-ERK, c-Met, and c-RAF1. When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared with controls, and inhibited pulmonary metastases by blocking c-Met, FAK, and MMP9 signaling. In contrast to 17-allylamino-17-demethoxygeldanamycin (17-AAG), PF4942847 did not induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. CONCLUSIONS: All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma. Clin Cancer Res; 22(10); 2520-33. ©2015 AACR.
Complete list of metadatas

Cited literature [50 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-01702294
Contributor : Sandrine Maurice <>
Submitted on : Tuesday, February 6, 2018 - 3:55:02 PM
Last modification on : Thursday, February 7, 2019 - 5:16:08 PM
Long-term archiving on: : Friday, May 25, 2018 - 10:28:45 PM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Benjamin Ory, Marc Baud 'Huin, Franck Verrecchia, Bénédicte Brounais-Le Royer, Thibaut Quillard, et al.. Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression. Clinical Cancer Research, American Association for Cancer Research, 2016, 22 (10), pp.2520 - 2533. ⟨10.1158/1078-0432.CCR-15-1925⟩. ⟨inserm-01702294⟩

Share

Metrics

Record views

120