阻断 HSP90 成瘾性抑制肿瘤细胞增殖、转移进展，并与唑来膦酸协同作用延缓骨肉瘤进展。

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

机构信息

Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France. INSERM, UMR 957, Nantes, France. LUNAM Université, Nantes, France. Equipe labellisée LIGUE 2012, Nantes, France.

出版信息

Clin Cancer Res. 2016 May 15;22(10):2520-33. doi: 10.1158/1078-0432.CCR-15-1925. Epub 2015 Dec 28.

DOI:10.1158/1078-0432.CCR-15-1925

PMID:26712686

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

摘要

目的

尽管骨肉瘤的治疗管理最近有所改善，但仍存在提高化疗反应的挑战，这需要开发新的策略来提高整体患者生存率。其中，HSP90 是一种分子伴侣，参与各种致癌蛋白的成熟和稳定，导致肿瘤细胞存活和疾病进展。我们评估了合成 HSP90 抑制剂 PF4942847 单独或联合唑来膦酸在骨肉瘤中的抗肿瘤特性。

实验设计

评估 PF4942847 对人骨肉瘤细胞生长和凋亡的影响。通过 Western blot 分析信号通路。在携带 HOS-MNNG 异种移植物的小鼠中评估 HSP90 治疗联合或不联合唑来膦酸对肿瘤生长、相关骨病变和肺转移的影响。评估 PF4942847 对人 CD14(+)单核细胞破骨细胞生成的影响。

结果

在骨肉瘤细胞系中，PF4942847 以剂量依赖性方式抑制细胞生长（IC50 ±50 nmol/L）并诱导细胞凋亡，导致亚 G1 部分和裂解 PARP 增加。这些生物学事件伴随着 Akt、p-ERK、c-Met 和 c-RAF1 表达的降低。当给荷骨肉瘤肿瘤的小鼠口服给药时，PF4942847 显著抑制肿瘤生长 80%，与对照组相比延长生存时间，并通过阻断 c-Met、FAK 和 MMP9 信号来抑制肺转移。与 17- 丙氨酸-17-脱甲氧基格尔德霉素（17-AAG）不同，PF4942847 不会诱导破骨细胞分化，并与唑来膦酸协同作用，延缓骨肉瘤进展并防止骨病变。