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  2. A novel ALK inhibitor ZYY inhibits Karpas299 cell growth in vitro and in a mouse xenograft model and induces protective autophagy

A novel ALK inhibitor ZYY inhibits Karpas299 cell growth in vitro and in a mouse xenograft model and induces protective autophagy

  • Toxicol Appl Pharmacol. 2019 Nov 15;383:114781. doi: 10.1016/j.taap.2019.114781.
Jiwei Shen 1 Junfang Wang 1 Jianan Du 1 Lijing Wang 1 Xuejiao Zhou 1 Xing Chang 1 Zengqiang Li 1 Xin Zhai 2 Daiying Zuo 3 Yingliang Wu 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zhaixin_syphu@126.com.
  • 3 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zuodaiying@163.com.
  • 4 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: yingliang_1016@163.com.
Abstract

In recent years, anaplastic lymphoma kinase (ALK) rearrangement-positive anaplastic large cell lymphoma (ALCL) has rising morbidity and mortality. Unfortunately, no ALK inhibitor has been approved by the FDA for single treatment of ALK rearrangement-positive ALCL. In this study, we investigated the antitumor effect of ZYY, a novel ALK inhibitor, showing a strong growth inhibitory effect on Karpas299 cells in vitro and in vivo. Specifically, ZYY significantly reduced the mRNA and protein expression of ALK and its downstream signaling proteins in Karpas299 cells. Furthermore, ZYY induced G1 phase arrest and promoted Apoptosis in Karpas299 cells. Furthermore, we demonstrated that ZYY-induced Apoptosis was mainly related to the mitochondria-dependent endogenous pathway. In vitro studies further showed that ZYY induced Autophagy in Karpas299 cells, along with increased levels of the autophagy-related proteins, including LC3II and Beclin-1. Moreover, knockdown Beclin-1 and application of Autophagy Inhibitor chloroquine potentiated ZYY-induced cytotoxicity and Apoptosis in vitro, indicating that cytoprotective Autophagy might be triggered by ZYY in Karpas299 cells. Taken together, the novel ALK inhibitor ZYY has tremendous potential for treating human ALCL, and a combination of Autophagy and ALK inhibition could effectively elicit potent antitumor effects.

Keywords

Anaplastic large cell lymphoma; Apoptosis; Autophagy; G1 arrest; Karpas299 cells; ZYY.

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