Rafat Sahar, Singh Prabhakar, Pandey Kamlesh Kumar, Almatroodi Saleh A, Alsahli Mohammed A, Almatroudi Ahmad, Rahmani Arshad Husain, Dev Kapil
Department of Biotechnology, Jamia Millia Islamia, New Delhi 110025, India.
Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110025, India.
Biology (Basel). 2022 Oct 27;11(11):1581. doi: 10.3390/biology11111581.
Cancer is the utmost common disease-causing death worldwide, characterized by uncontrollable cell division with the potential of metastasis. Overexpression of the Inhibitors of Apoptosis proteins (IAPs) and autophagy correlates with tumorigenesis, therapeutic resistance, and reoccurrence after anticancer therapies. This study illuminates the role and efficacy of smac mimetic compound BV6 alone and in co-treatment with death ligands such as TRAIL and TNFα in the regulation of cell death mechanisms, i.e., apoptosis and autophagy. In this study, MTT assays, wound healing assays, and cellular and nuclear morphological studies were done. DAPI staining, AO/EtBr staining and AnnexinV/PI FACS was done to study the apoptosis. The expression of IAPs and autophagy biomarkers was analyzed using Real time-PCR and western blotting. Meanwhile, TEM demonstrated autophagy and cellular autophagic vacuoles in response to the BV6. The result shows a promising anti-cancer effect of BV6 alone as well as in combinational treatment with TRAIL and TNFα, compared to the lone treatment of TRAIL and TNFα in both breast cancer cell lines. The smac mimetic compound might provide an alternative combinational therapy with conventional anticancer therapies to tackle their inefficiency at the advanced stage of cancer, cancer resistance, and reoccurrence. Also, IAPs and autophagic proteins could act as potent target molecules for the development of novel anti-cancer drugs in pathogenesis and the betterment of regimens for cancer.
癌症是全球范围内导致死亡的最常见疾病，其特征是细胞不可控分裂并具有转移潜力。凋亡抑制蛋白（IAPs）的过表达和自噬与肿瘤发生、治疗耐药性以及抗癌治疗后的复发相关。本研究阐明了smac模拟化合物BV6单独以及与死亡配体如TRAIL和TNFα联合治疗在调节细胞死亡机制（即凋亡和自噬）中的作用和疗效。在本研究中，进行了MTT试验、伤口愈合试验以及细胞和细胞核形态学研究。采用DAPI染色、AO/EtBr染色和AnnexinV/PI流式细胞术研究凋亡。使用实时PCR和蛋白质印迹分析IAPs和自噬生物标志物的表达。同时，透射电子显微镜（TEM）显示了对BV6有反应的自噬和细胞自噬泡。结果表明，与单独使用TRAIL和TNFα治疗相比，BV6单独以及与TRAIL和TNFα联合治疗在两种乳腺癌细胞系中均显示出有前景的抗癌效果。smac模拟化合物可能为传统抗癌治疗提供一种替代联合疗法，以解决其在癌症晚期的低效性、癌症耐药性和复发问题。此外，IAPs和自噬蛋白可作为开发新型抗癌药物的有效靶分子，用于癌症发病机制研究和优化癌症治疗方案。
