Division of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, U.S.A.
Department of Biology, College of Science and Technology, Florida A&M University, Tallahassee, FL, U.S.A.
Cancer Genomics Proteomics. 2023 Jul-Aug;20(4):323-342. doi: 10.21873/cgp.20385.
BACKGROUND/AIM: Chemotherapy resistance in triple-negative breast cancer (TNBC) cells is well documented. Therefore, it is necessary to develop safer and more effective therapeutic agents to enhance the outcomes of chemotherapeutic agents. The natural alkaloid sanguinarine (SANG) has demonstrated therapeutic synergy when coupled with chemotherapeutic agents. SANG can also induce cell cycle arrest and trigger apoptosis in various cancer cells. MATERIALS AND METHODS: In this study, we investigated the molecular mechanism underlying SANG activity in MDA-MB-231 and MDA-MB-468 cells as two genetically different models of TNBC. We employed various assays including Alamar Blue to measure the effect of SANG on cell viability and proliferation rate, flow cytometry analysis to study the potential of the compound to induce apoptosis and cell cycle arrest, quantitative qRT PCR apoptosis array to measure the expression of different genes mediating apoptosis, and the western system was used to analyze the impact of the compound on AKT protein expression. RESULTS: SANG lowered cell viability and disrupted cell cycle progression in both cell lines. Furthermore, S-phase cell cycle arrest-mediated apoptosis was found to be the primary contributor to cell growth inhibition in MDA-MB-231 cells. SANG-treated TNBC cells showed significantly up-regulated mRNA expression of 18 genes associated with apoptosis, including eight TNF receptor superfamily (TNFRSF), three members of the BCL2 family, and two members of the caspase (CASP) family in MDA-MB-468 cells. In MDA-MB-231 cells, two members of the TNF superfamily and four members of the BCL2 family were affected. The western study data showed the inhibition of AKT protein expression in both cell lines concurrent with up-regulated BCL2L11 gene. Our results point to the AKT/PI3K signaling pathway as one of the key mechanisms behind SANG-induced cell cycle arrest and death. CONCLUSION: SANG shows anticancer properties and apoptosis-related gene expression changes in the two TNBC cell lines and suggests AKT/PI3K pathway implication in apoptosis induction and cell cycle arrest. Thus, we propose SANG's potential as a solitary or supplementary treatment agent against TNBC.
背景/目的：三阴性乳腺癌（TNBC）细胞的化疗耐药性已得到充分证实。因此，有必要开发更安全、更有效的治疗药物来增强化疗药物的疗效。天然生物碱血根碱（SANG）与化疗药物联合使用时表现出治疗协同作用。SANG 还可以诱导各种癌细胞的细胞周期停滞和触发细胞凋亡。
材料和方法：在这项研究中，我们研究了 SANG 在 MDA-MB-231 和 MDA-MB-468 细胞中的活性的分子机制，这两种细胞系是 TNBC 的两种具有不同遗传背景的模型。我们采用了各种检测方法，包括 Alamar Blue 检测来测量 SANG 对细胞活力和增殖率的影响，流式细胞术分析来研究化合物诱导细胞凋亡和细胞周期停滞的潜力，定量 qRT-PCR 凋亡阵列来测量不同基因介导的凋亡的表达，以及 Western 系统来分析化合物对 AKT 蛋白表达的影响。
结果：SANG 降低了两种细胞系的细胞活力并扰乱了细胞周期进程。此外，S 期细胞周期停滞介导的细胞凋亡被发现是 MDA-MB-231 细胞中抑制细胞生长的主要原因。用 SANG 处理的 TNBC 细胞显示与凋亡相关的 18 个基因的 mRNA 表达显著上调，包括 MDA-MB-468 细胞中的 8 个 TNF 受体超家族（TNFRSF）、3 个 BCL2 家族成员和 2 个半胱氨酸天冬氨酸蛋白酶（CASP）家族成员，而在 MDA-MB-231 细胞中，有两个 TNF 超家族成员和四个 BCL2 家族成员受到影响。Western 研究数据显示，两种细胞系中 AKT 蛋白表达受到抑制，同时 BCL2L11 基因上调。我们的研究结果表明，AKT/PI3K 信号通路是 SANG 诱导细胞周期停滞和死亡的关键机制之一。
结论：SANG 在两种 TNBC 细胞系中表现出抗癌特性和与细胞凋亡相关的基因表达变化，并表明 AKT/PI3K 途径在细胞凋亡诱导和细胞周期停滞中的作用。因此，我们提出 SANG 作为单独或辅助治疗 TNBC 的潜在药物。
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