Mehraj Umar, Wani Nissar Ahmad, Hamid Abid, Alkhanani Mustfa, Almilaibary Abdullah, Mir Manzoor Ahmad
Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, J&K, India.
Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
Front Pharmacol. 2022 Aug 8;13:958443. doi: 10.3389/fphar.2022.958443. eCollection 2022.
Although advances in diagnostics and therapeutics have prolonged the survival of triple-negative breast cancer (TNBC) patients, metastasis, therapeutic resistance, and lack of targeted therapies remain the foremost hurdle in the effective management of TNBC. Thus, evaluation of new therapeutic agents and their efficacy in combination therapy is urgently needed. The third-generation retinoid adapalene (ADA) has potent antitumor activity, and using ADA in combination with existing therapeutic regimens may improve the effectiveness and minimize the toxicities and drug resistance. The current study aimed to assess the anticancer efficacy of adapalene as a combination regimen with the PI3K inhibitor (GDC-0941) in TNBC models. The Chou-Talalay's method evaluated the pharmacodynamic interactions (synergism, antagonism, or additivity) of binary drug combinations. Flow cytometry, Western blotting, and studies were used to analyze the mechanism of GDC-ADA synergistic interactions in TNBC cells. The combination of GDC and ADA demonstrated a synergistic effect in inhibiting proliferation, migration, and colony formation of tumor cells. Accumulation of reactive oxygen species upon co-treatment with GDC and ADA promoted apoptosis and enhanced sensitivity to GDC in TNBC cells. The findings indicate that ADA is a promising therapeutic agent in treating advanced BC tumors and enhance sensitivity to GDC in inhibiting tumor growth in TNBC models while reducing therapeutic resistance.
尽管诊断和治疗方面的进展延长了三阴性乳腺癌（TNBC）患者的生存期，但转移、治疗耐药性以及缺乏靶向治疗仍然是有效管理TNBC的首要障碍。因此，迫切需要评估新的治疗药物及其在联合治疗中的疗效。第三代维甲酸阿达帕林（ADA）具有强大的抗肿瘤活性，将ADA与现有治疗方案联合使用可能会提高疗效，并将毒性和耐药性降至最低。本研究旨在评估阿达帕林与PI3K抑制剂（GDC-0941）联合用药方案在TNBC模型中的抗癌疗效。采用Chou-Talalay方法评估二元药物组合的药效学相互作用（协同、拮抗或相加）。运用流式细胞术、蛋白质印迹法及相关研究分析GDC-ADA在TNBC细胞中的协同相互作用机制。GDC与ADA联合使用在抑制肿瘤细胞增殖、迁移和集落形成方面显示出协同作用。GDC与ADA共同处理后活性氧的积累促进了TNBC细胞的凋亡，并增强了对GDC的敏感性。研究结果表明，ADA是治疗晚期乳腺癌肿瘤的一种有前景的治疗药物，在TNBC模型中可增强对GDC抑制肿瘤生长的敏感性，同时降低治疗耐药性。
