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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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Effects of QSN-10c on mitochondrial membrane potential and expression of mitochondria-related apoptotic proteins. (A–B) The mitochondrial membrane potential of K562 cells treated with QSN-10c was decreased in a dose-dependent manner. (C) Treatment of cells with various concentrations of QSN-10c for 48 h resulted in dose-dependent increase in the release of cytochrome c, and in the expression of Bax. The level of Bcl-2 was decreased in a dose-dependent manner.
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fig4: Effects of QSN-10c on mitochondrial membrane potential and expression of mitochondria-related apoptotic proteins. (A–B) The mitochondrial membrane potential of K562 cells treated with QSN-10c was decreased in a dose-dependent manner. (C) Treatment of cells with various concentrations of QSN-10c for 48 h resulted in dose-dependent increase in the release of cytochrome c, and in the expression of Bax. The level of Bcl-2 was decreased in a dose-dependent manner.

Mentions: Many anti-neoplastic drugs induce apoptosis in cancer cells via the mitochondrial apoptotic pathway26,27,28,29. A hallmark of death induction via this pathway is a rapid and early loss of the mitochondrial membrane potential (Δψm). Thus, we analyzed the integrity of mitochondrial function after treatment with QSN-10c. QSN-10c treatment resulted in a significant concentration-dependent breakdown of the Δψm (Figure 4A, 48 h after treatment with 50, 100, or 150 μmol/L QSN-10c). HUVEC cells treated with QSN-10c showed no change in Δψm (Figure 4B).


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)

Effects of QSN-10c on mitochondrial membrane potential and expression of mitochondria-related apoptotic proteins. (A–B) The mitochondrial membrane potential of K562 cells treated with QSN-10c was decreased in a dose-dependent manner. (C) Treatment of cells with various concentrations of QSN-10c for 48 h resulted in dose-dependent increase in the release of cytochrome c, and in the expression of Bax. The level of Bcl-2 was decreased in a dose-dependent manner.
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Related In: Results  -  Collection

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fig4: Effects of QSN-10c on mitochondrial membrane potential and expression of mitochondria-related apoptotic proteins. (A–B) The mitochondrial membrane potential of K562 cells treated with QSN-10c was decreased in a dose-dependent manner. (C) Treatment of cells with various concentrations of QSN-10c for 48 h resulted in dose-dependent increase in the release of cytochrome c, and in the expression of Bax. The level of Bcl-2 was decreased in a dose-dependent manner.
Mentions: Many anti-neoplastic drugs induce apoptosis in cancer cells via the mitochondrial apoptotic pathway26,27,28,29. A hallmark of death induction via this pathway is a rapid and early loss of the mitochondrial membrane potential (Δψm). Thus, we analyzed the integrity of mitochondrial function after treatment with QSN-10c. QSN-10c treatment resulted in a significant concentration-dependent breakdown of the Δψm (Figure 4A, 48 h after treatment with 50, 100, or 150 μmol/L QSN-10c). HUVEC cells treated with QSN-10c showed no change in Δψm (Figure 4B).

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