Original Article

Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition

Authors: Wen-wen Lv, Si-ning Qin, Cong-qin Chen, Jin-jie Zhang, Tian-shu Ren, Yong-nan Xu, Qing-chun Zhao
DOI: 10.1038/aps.2013.194

Abstract

Wen-wen LV1, 2, Si-ning QIN2, Cong-qin CHEN2, Jin-jie ZHANG2, Tian-shu REN1, Yong-nan XU2, *, Qing-chun ZHAO1, *
1Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, China; 2Shenyang Pharmaceutical University, Shenyang 110016, China

Aim: 2-(4,6-Dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c) is one of isoindolone derivatives with antiproliferative activity against human umbilical vein endothelial cells (HUVECs). The aim of this study was to investigate its antitumor activity in vitro and anti-angiogenic effects in vitro and in vivo.

Methods:K562 leukemic cells and HUVECs were used for in vitro studies. Cell viability was examined using MTT assay. Cell apoptosis and mitochondrial transmembrane potential (Δψm) were detected with flow cytometry. Tube formation and migration of HUVECs were studied using two-dimensional Matrigel assay and wound-healing migration assay, respectively. VEGF levels were analyzed with RT-PCR and Western blotting. A zebrafish embryo model was used for in vivo anti-angiogenic studies. The molecular mechanisms for apoptosis in K562 cells and antiangiogenesis were measured with Western blotting.

Results: In antitumor activity studies, QSN-10c suppressed the viability of K562 cells and induced apoptosis in dose- and time-dependent manners. Furthermore, QSN-10c dose-dependently decreased the Δψm in K562 cells, increased the release of cytochrome c and the level of Bax, and decreased the level of Bcl-2, suggesting that QSN-10c-induced apoptosis of K562 cells was mediated via the mitochondrial apoptotic pathway. In anti-angiogenic activity studies, QSN-10c suppressed the viability of HUVECs and induced apoptosis in dose dependent manners. QSN-10c treatment did not alter the Δψm in HUVECs, but dose-dependently inhibited the expression of VEGF, inhibited the tube formation and cell migration in vitro, and significantly suppressed the number of ISVs in zebrafish embryos in vivo. Furthermore, QSN-10c dose-dependently suppressed the phosphorylation of AKT and GSK3β in both HUVECs and K562 cells.

Conclusion: QSN-10c is a novel antitumor compound that exerts both antitumor and anti-angiogenic effects via inhibiting the PI3K/AKT/GSK3β signaling pathway.


Keywords: isoindolone; anticancer drug; leukemia; zebrafish; angiogenesis; apoptosis; AKT; GSK3β

The authors are very grateful to Yan-qiang YUAN from the Biology Institute of Shandong Academy of Sciences for providing the zebrafish embryo research platform.
* To whom correspondence should be addressed.
E-mail zhaoqingchun1967@163.com (Qing-chun ZHAO);ynxucn@syphu.edu.cn (Yong-nan XU)
Received 2013-09-10 Accepted 2013-12-19
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