BCL-2 Inhibitor Venetoclax Induces Autophagy-Associated Cell Death, Cell Cycle Arrest, and Apoptosis in Human Breast Cancer Cells.
BCL-2 Inhibitor Venetoclax Induces Autophagy-Associated Cell Death, Cell Cycle Arrest, and Apoptosis in Human Breast Cancer Cells.
复制标题
BCL-2抑制剂Venetoclax诱导人乳腺癌细胞自噬相关的细胞死亡、细胞周期阻滞和凋亡
DOI：
10.2147/ott.s281519
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发表时间：
2020
影响因子：
4
通讯作者：
Korashy HM
中科院分区：
文献类型：
--
作者：
Alhoshani A;Alatawi FO;Al-Anazi FE;Attafi IM;Zeidan A;Agouni A;El Gamal HM;Shamoon LS;Khalaf S;Korashy HM
维奈托克（VCX）是一种选择性BCL-2抑制剂，被批准用于治疗白血病和淋巴瘤。然而，VCX单独或与其他化疗药物联合治疗乳腺癌的作用机制尚需进一步研究。用不同浓度的VCX处理具有不同分子亚型（MDA-MB-231、MCF-7和SKBR-3）的乳腺癌细胞系指定的时间点。通过qRT-PCR和Western印迹分析确定细胞增殖、凋亡和自噬基因的表达。此外，MDA-MB-231细胞发生凋亡的百分比，表达更高的氧化应激水平，并通过流式细胞术测定细胞周期时相的变化。用增加浓度的VCX处理人乳腺癌细胞引起细胞生长和增殖的显著降低。这种作用与凋亡MDA-MB-231细胞百分比和凋亡基因caspase 3、caspase 7和BAX表达的显著增加以及抗凋亡基因BCL-2水平的抑制相关。VCX处理诱导细胞凋亡诱导细胞周期停滞在G 0/G1期，细胞增殖因子基因，细胞周期蛋白D1和E2 F1的抑制。此外，VCX处理增加了活性氧的形成和自噬标记物Beclin 1和LC 3-II的表达水平。重要的是，VCX引起的这些细胞变化增加了MDA-MB-231细胞对阿霉素的化学敏感性。本研究通过诱导细胞凋亡、细胞周期阻滞和自噬来探讨VCX介导的对TNBC MDA-MB-231细胞生长和增殖的抑制作用的分子机制。该研究还探索了BCL-2作为乳腺癌新靶向治疗的作用。
Venetoclax (VCX) is a selective BCL-2 inhibitor approved for the treatment of leukemia and lymphoma. However, the mechanisms of anti-cancer effect of VCX either as a monotherapy or in combination with other chemotherapeutic agents against breast cancer need investigation. Breast cancer cell lines with different molecular subtypes (MDA-MB-231, MCF-7, and SKBR-3) were treated with different concentrations of VCX for indicated time points. The expression of cell proliferative, apoptotic, and autophagy genes was determined by qRT-PCR and Western blot analyses. In addition, the percentage of MDA-MB-231 cells underwent apoptosis, expressed higher oxidative stress levels, and the changes in the cell cycle phases were determined by flow cytometry. Treatment of human breast cancer cells with increasing concentrations of VCX caused a significant decrease in cells growth and proliferation. This effect was associated with a significant increase in the percentage of apoptotic MDA-MB-231 cells and in the expression of the apoptotic genes, caspase 3, caspase 7, and BAX, with inhibition of anti-apoptotic gene, BCL-2 levels. Induction of apoptosis by VCX treatment induced cell cycle arrest at G0/G1 phase with inhibition of cell proliferator genes, cyclin D1 and E2F1. Furthermore, VCX treatment increased the formation of reactive oxygen species and the expression level of autophagy markers, Beclin 1 and LC3-II. Importantly, these cellular changes by VCX increased the chemo-sensitivity of MDA-MB-231 cells to doxorubicin. The present study explores the molecular mechanisms of VCX-mediated inhibitory effects on the growth and proliferation of TNBC MDA-MB-231 cells through the induction of apoptosis, cell cycle arrest, and autophagy. The study also explores the role of BCL-2 as a novel targeted therapy for breast cancer.