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

Lv WW, Qin SN, Chen CQ, Zhang JJ, Ren TS, Xu YN, Zhao QC - Acta Pharmacol. Sin. (2014)

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

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, China [2] Shenyang Pharmaceutical University, Shenyang 110016, China.

ABSTRACT

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.

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The chemical structures of 4,6-dihydroxyisoindol-1,3-dione, thalidomide and QSN-10c.
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fig1: The chemical structures of 4,6-dihydroxyisoindol-1,3-dione, thalidomide and QSN-10c.

Mentions: In our search for tumor inhibitors from natural sources, we identified 4,6-dihydroxyisoindol-1,3-dione (Figure 1) as a new compound isolated from Lasiosphaera fenzlii Reich. Our previous studies demonstrated that this compound has enhanced anti-angiogenic activity compared with thalidomide via inhibition of VEGF secretion. However, the compound exhibits only a slight inhibitory effect on tumor cell proliferation19. To find a compound with antitumor and anti-angiogenic activities in vitro, a series of isoindolone derivatives were subsequently synthesized, and their cytotoxicities were preliminarily evaluated in A549 and HUVEC cells. A new compound, 2-(4,6-dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c, Figure 1), demonstrated moderate antiproliferative activities in HUVECs20. The purpose of the present study is to examine the effects of QSN-10c on angiogenesis in vitro (VEGF expression, tube formation, and HUVEC migration) and in vivo (zebra embryo model) as well as the possible mechanisms involved [phosphorylation of proteins involved in the AKT signaling pathway and the mitogen-activated protein kinase pathway (MAPK)]. In addition, QSN-10c also demonstrated enhanced cytotoxicity in K562 leukemic cells in our antitumor screening. Consequently, the mechanism for apoptotic induction in K562 cells is also reported here.


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

Lv WW, Qin SN, Chen CQ, Zhang JJ, Ren TS, Xu YN, Zhao QC - Acta Pharmacol. Sin. (2014)

The chemical structures of 4,6-dihydroxyisoindol-1,3-dione, thalidomide and QSN-10c.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814032&req=5

fig1: The chemical structures of 4,6-dihydroxyisoindol-1,3-dione, thalidomide and QSN-10c.
Mentions: In our search for tumor inhibitors from natural sources, we identified 4,6-dihydroxyisoindol-1,3-dione (Figure 1) as a new compound isolated from Lasiosphaera fenzlii Reich. Our previous studies demonstrated that this compound has enhanced anti-angiogenic activity compared with thalidomide via inhibition of VEGF secretion. However, the compound exhibits only a slight inhibitory effect on tumor cell proliferation19. To find a compound with antitumor and anti-angiogenic activities in vitro, a series of isoindolone derivatives were subsequently synthesized, and their cytotoxicities were preliminarily evaluated in A549 and HUVEC cells. A new compound, 2-(4,6-dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c, Figure 1), demonstrated moderate antiproliferative activities in HUVECs20. The purpose of the present study is to examine the effects of QSN-10c on angiogenesis in vitro (VEGF expression, tube formation, and HUVEC migration) and in vivo (zebra embryo model) as well as the possible mechanisms involved [phosphorylation of proteins involved in the AKT signaling pathway and the mitogen-activated protein kinase pathway (MAPK)]. In addition, QSN-10c also demonstrated enhanced cytotoxicity in K562 leukemic cells in our antitumor screening. Consequently, the mechanism for apoptotic induction in K562 cells is also reported here.

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

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, China [2] Shenyang Pharmaceutical University, Shenyang 110016, China.

ABSTRACT

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.

Show MeSH