1. Academic Validation
  2. The anti-osteosarcoma cell activity by a mTORC1/2 dual inhibitor RES-529

The anti-osteosarcoma cell activity by a mTORC1/2 dual inhibitor RES-529

  • Biochem Biophys Res Commun. 2018 Mar 4;497(2):499-505. doi: 10.1016/j.bbrc.2018.02.050.
Xujun Hu 1 Zirui Wang 2 Meikai Chen 1 Xuerong Chen 1 Wenqing Liang 3
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China.
  • 2 East Medical Area, Internal Medicine Ward, Linyi People's Hospital, Linyi City, Shandong, China.
  • 3 Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China. Electronic address: liangwqgk9@163.com.
Abstract

mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced Apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation. Significantly, RES-529 induced Reactive Oxygen Species (ROS) production and mitochondrial depolarization in U2OS cells as well. RES-529-induced anti-OS cell activity was more potent than other known Akt-mTOR inhibitors. In vivo, RES-529 intraperitoneal injection significantly inhibited U2OS xenograft tumor growth in severe combined immunodeficiency (SCID) mice. mTORC1/2 activation in RES-529-treated tumor tissues was largely inhibited. Collectively, the mTOR Inhibitor RES-529 efficiently inhibits human OS cell growth in vitro and in vivo.

Keywords

Akt and molecularly-targeted therapy; Osteosarcoma; RES-529; mTOR.

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