Gökşen Tosun Nazan, Kaplan Özlem
Tokat Vocational School of Health Services, Department of Medical Services and Techniques, Tokat Gaziosmanpaşa University, Tokat, Turkey.
Rafet Kayış Faculty of Engineering, Department of Genetics and Bioengineering, Alanya Alaaddin Keykubat University, Antalya, Turkey.
Breast Cancer Res Treat. 2025 Apr;210(2):493-506. doi: 10.1007/s10549-024-07587-1. Epub 2025 Jan 9.
The incidence of breast cancer has been increasing in recent years, and monotherapy approaches are not sufficient alone in the treatment of breast cancer. In the combined therapy approach, combining two or three different agents in lower doses can mitigate the side effects on living cells and tissues caused by high doses of chemical agents used alone. ABT-263 (navitoclax), a clinically tested Bcl-2 family protein inhibitor, has shown limited success in clinical trials due to the development of resistance to monotherapy in breast cancer cells. This resistance shows that monotherapy approaches are inadequate and more effective treatment strategies are needed. It is the ability of HSP90 inhibitors to destabilize many oncoproteins that are critical for the survival of cancer cells. This study aimed to examine the anticancer activity of the combination of ABT-263 with BIIB021, a new generation HSP90 inhibitor, on two widely used breast cancer cell lines: MCF-7 (ER-positive) and MDA-MB-231 (triple-negative breast cancer, TNBC). These cell lines were selected to represent distinct breast cancer subtypes with different molecular characteristics and clinical behaviors.
Single and combined cytotoxic effects of this agents on MCF-7 and MDA-MB-231 breast cancer cell lines were determined using the MTT cell viability test. The combined use of these two agents showed a synergistic effect, and this effect was assigned using the Chou and Talalay method. mRNA and protein levels of apoptosis-related genes Bax, Bcl-2, Casp9, and Heat Shock Proteins HSP27, HSP70, and HSP90 were analyzed using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western Blotting, respectively.
The cytotoxicity analysis, combined with the application of the Chou-Talalay method, demonstrated that the BIIB021 and ABT-263 combination exhibited significantly greater anticancer activity compared to the individual effects of either BIIB021 or ABT-263 in breast cancer cell lines. The analysis of mRNA and protein levels indicated that the BIIB021+ABT-263 combination may have triggered the intrinsic apoptotic pathway in breast cancer cells.
This study showed that co-administration of ABT-263 and BIIB021 agents exhibited synergistic cytotoxic effects and increased the expression of apoptosis-related genes in breast cancer cell lines.
近年来乳腺癌的发病率一直在上升，单一疗法在乳腺癌治疗中单独使用并不充分。在联合治疗方法中，将两三种不同药物以较低剂量联合使用可以减轻单独使用高剂量化学药物对活细胞和组织产生的副作用。ABT-263（纳维托克司）是一种经过临床试验的Bcl-2家族蛋白抑制剂，由于乳腺癌细胞对单一疗法产生耐药性，在临床试验中取得的成功有限。这种耐药性表明单一疗法并不充分，需要更有效的治疗策略。HSP90抑制剂能够使许多对癌细胞存活至关重要的癌蛋白不稳定。本研究旨在检测ABT-263与新一代HSP90抑制剂BIIB021联合使用对两种广泛应用的乳腺癌细胞系的抗癌活性：MCF-7（雌激素受体阳性）和MDA-MB-231（三阴性乳腺癌，TNBC）。选择这些细胞系来代表具有不同分子特征和临床行为的不同乳腺癌亚型。
使用MTT细胞活力试验测定这些药物对MCF-7和MDA-MB-231乳腺癌细胞系的单一和联合细胞毒性作用。这两种药物的联合使用显示出协同作用，并使用Chou和Talalay方法确定了这种作用。分别使用定量实时聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法分析凋亡相关基因Bax、Bcl-2、Casp9以及热休克蛋白HSP27、HSP70和HSP90的mRNA和蛋白质水平。
细胞毒性分析结合Chou-Talalay方法的应用表明，与BIIB021或ABT-263单独作用相比，BIIB021与ABT-263联合使用在乳腺癌细胞系中表现出显著更强的抗癌活性。mRNA和蛋白质水平分析表明，BIIB021 + ABT-263联合使用可能触发了乳腺癌细胞中的内源性凋亡途径。
本研究表明，ABT-263和BIIB021联合给药在乳腺癌细胞系中表现出协同细胞毒性作用，并增加了凋亡相关基因的表达。
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