Babaei Zeinab, Amani Mahdi, Minaiyan Mohsen, Ghorbanhosseini Seyedeh Sara, Aghaei Mahmoud
Department of Clinical Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Res Pharm Sci. 2024 Oct 22;19(5):549-560. doi: 10.4103/RPS.RPS_245_23. eCollection 2024 Oct.
The new plan of using molecular targeted agents in combination with cytotoxic drugs may represent a promising strategy to increase the efficacy of chemotherapy. Hence, we examined whether α2β1 integrin-specific inhibitor, BTT-3033, could modulate the susceptibility of OVCAR3 and SKOV3 ovarian cancer cells to paclitaxel (PTX).
Ovarian cancer cell lines were treated with BTT-3033 and different concentrations of PTX. To determine the mechanisms involved in the PTX/BTT-3033 combination-induced cell death, cell viability, apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and caspase-3 activity were evaluated.
FINDINGS/RESULTS: Both BTT-3033 (≥ 1 μM) and PTX (≥ 0.01 μM) suppressed the proliferation of OVCAR3 and SKOV3 cells in a concentration-related manner. Pretreatment with BTT-3033 (1 μM), followed by PTX-induced synergistic antiproliferative effects, decreased the IC values of PTX from 0.45 to 0.03 μM in OVCAR3 and 0.35 to 0.02 μM in SKOV3 cells. All of the coefficients of drug interaction for various PTX and BTT-3033 combinations were found to be less than 1. Moreover, PTX/BTT-3033 combination induced more apoptotic cells (from 4.2% to 87.0% in OVCAR3 and 2.4% to 88.5% in SKOV3) than PTX alone. Combination therapy also decreased MMP and increased the caspase-3 activity. Additionally, we found that the PTX/BTT-3033 combination enhanced ROS production in OVCAR3 and SKOV3 cells.
BTT-3033 has demonstrated the ability to enhance the susceptibility of ovarian cancer cells to PTX by inducing MMP loss, ROS production, and mitochondrial apoptosis, therefore this combination therapy might represent a promising strategy for ovarian cancer treatment.
使用分子靶向药物联合细胞毒性药物的新方案可能是提高化疗疗效的一种有前景的策略。因此，我们研究了α2β1整合素特异性抑制剂BTT-3033是否能调节OVCAR3和SKOV3卵巢癌细胞对紫杉醇（PTX）的敏感性。
用BTT-3033和不同浓度的PTX处理卵巢癌细胞系。为了确定PTX/BTT-3033联合诱导细胞死亡所涉及的机制，评估了细胞活力、凋亡、活性氧（ROS）产生、线粒体膜电位（MMP）和半胱天冬酶-3活性。
BTT-3033（≥1μM）和PTX（≥0.01μM）均以浓度相关的方式抑制OVCAR3和SKOV3细胞的增殖。用BTT-3033（1μM）预处理，随后PTX诱导协同抗增殖作用，使PTX在OVCAR3细胞中的IC值从0.45μM降至0.03μM，在SKOV3细胞中从0.35μM降至0.02μM。发现各种PTX和BTT-3033组合的所有药物相互作用系数均小于1。此外，PTX/BTT-3033联合诱导的凋亡细胞比单独使用PTX更多（在OVCAR3细胞中从4.2%增至87.0%，在SKOV3细胞中从2.4%增至88.5%）。联合治疗还降低了MMP并增加了半胱天冬酶-3活性。此外，我们发现PTX/BTT-3033联合增强了OVCAR3和SKOV3细胞中的ROS产生。
BTT-3033已证明能够通过诱导MMP丧失、ROS产生和线粒体凋亡来增强卵巢癌细胞对PTX的敏感性，因此这种联合治疗可能是卵巢癌治疗的一种有前景的策略。
