Abstract
Targeting oncogenic proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer research. Bromodomain and extra-terminal (BET) family proteins are newly identified cancer-related epigenetic regulators, which have a role in the pathogenesis and progression of osteosarcoma. In this study, we investigated the in vitro and in vivo anti-osteosarcoma activity by targeting BET with a PROTAC molecule BETd-260. The results showed that BETd-260 completely depletes BET proteins and potently suppresses cell viability in MNNG/HOS, Saos-2, MG-63, and SJSA-1 osteosarcoma cell lines. Compared with BET inhibitors HJB-97 and JQ1, the activity of BETd-260 increased over 1000 times. Moreover, BETd-260 substantially inhibited the expression of anti-apoptotic Mcl-1, Bcl-xl while increased the expression of pro-apoptotic Noxa, which resulted in massive apoptosis in osteosarcoma cells within hours. In addition, pro-oncogenic protein c-Myc also was substantially inhibited by BETd-260 in the OS cells. Of note, BETd-260 induced degradation of BET proteins, triggered apoptosis in xenograft osteosarcoma tumor tissue, and profoundly inhibited the growth of cell-derived and patient-derived osteosarcoma xenografts in mice. Our findings indicate that BET PROTACs represent a promising therapeutic agent for human osteosarcoma.
Highlights
Osteosarcoma (OS) is the most common type of primary malignant bone tumor, predominantly affecting the health and life of children and young adults[1]
The results showed that BETd-260 potently and dose-dependently inhibited cell viability in all four OS cell lines with low nanomolar EC50 values
Because the Bcl-2 family of proteins plays a key role in the initiation and execution of apoptosis, we investigated whether the robust apoptotic activity of BETd-260 in OS cells was associated with the modification of these key apoptotic proteins
Summary
Osteosarcoma (OS) is the most common type of primary malignant bone tumor, predominantly affecting the health and life of children and young adults[1]. Current treatment measures for OS include surgical resection and adjuvant chemotherapy. These conventional treatments offer a significant survival advantage in patients with localized OS2. Patients with metastasized or recurrent OS often do not respond adequately to these standard treatments. BET inhibitor JQ1 as a single agent or in combination with other anticancer agents leads to anti-proliferative activity and modestly inhibits OS xenograft tumor growth[9,10,11]. This suggests that targeting BET may have beneficial effects for OS patients
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