Pasha Akbar, Ravinder Doneti, Pawar Smita C
Department of Genetics & Biotechnology, University College of Science, Osmania University, Hyderabad, Telangana, India.
Drug Dev Res. 2025 Feb;86(1):e70052. doi: 10.1002/ddr.70052.
Drug resistance and cancer recurrence are major cause of Cervical cancer (CC) patient mortality. Cisplatin (CDDP) is the major drug that has been extremely used in all stages in treating CC, although relapse and malignant instances have been observed as a result of cisplatin resistance in CC. In the present study, we established Cisplatin resistant CC HeLa cell line model and the cytotoxic effects of Andro as a single agent or in combination with CDDP were investigated to assess its potential as a chemotherapeutic agent in cisplatin-resistant HeLa (CisR-HeLa) cells. Andro enhanced the cytotoxicity of CDDP in CisR-HeLa cells and shown a synergistic effect by reducing cell viability, proliferation, migration, invasion, and inducing apoptosis in cisplatin resistant cells. Furthermore, we evaluated the expression levels of inflammatory and oncogenic proteins, SPP1, NF-kB, iNOS, COX-2, and the PI3K/AKT signaling pathway, which are associated with cisplatin resistance, as well as using Andro to regulate the targeted markers in CisR-HeLa cells to overcome resistance. The results show that suppressing SPP1 and NF-kB by Andro alone or in combination with CDDP regulates iNOS, COX-2, and increases PTEN expression. The addition of Andro to CDDP inhibited PI3K and AKT expression as well as triggered synergistic apoptosis, which could be associated with variations in Bax and Bcl-2 protein levels. The results suggest that Andro in combination with CDDP exhibits synergistic anti-tumor growth efficacy that targets multiple inflammatory markers, resulting in a promising treatment option for individuals with recurrent cancer due to drug resistance and advanced CC.
耐药性和癌症复发是宫颈癌（CC）患者死亡的主要原因。顺铂（CDDP）是治疗CC各阶段中广泛使用的主要药物，尽管由于CC中的顺铂耐药性已观察到复发和恶性情况。在本研究中，我们建立了顺铂耐药的CC HeLa细胞系模型，并研究了雄激素单独或与CDDP联合使用的细胞毒性作用，以评估其作为顺铂耐药HeLa（CisR-HeLa）细胞中化疗药物的潜力。雄激素增强了CDDP在CisR-HeLa细胞中的细胞毒性，并通过降低顺铂耐药细胞的活力、增殖、迁移、侵袭和诱导凋亡显示出协同作用。此外，我们评估了与顺铂耐药相关的炎症和致癌蛋白SPP1、NF-κB、iNOS、COX-2以及PI3K/AKT信号通路的表达水平，并使用雄激素调节CisR-HeLa细胞中的靶向标志物以克服耐药性。结果表明，雄激素单独或与CDDP联合抑制SPP1和NF-κB可调节iNOS、COX-2，并增加PTEN表达。在CDDP中添加雄激素可抑制PI3K和AKT表达，并引发协同凋亡，这可能与Bax和Bcl-2蛋白水平的变化有关。结果表明，雄激素与CDDP联合表现出针对多种炎症标志物的协同抗肿瘤生长功效，为因耐药性和晚期CC导致的复发性癌症患者提供了一种有前景的治疗选择。
