Vilarullo Roman, Casco María Del Pilar, Mares Ahlers María Candelaria, Gottifredi Vanesa, Balcone Lara, Maggio Julian, Mengual Gomez Diego Luis, Gomez Daniel Eduardo, Armando Romina Gabriela
Molecular Oncology Unit, Center of Molecular and Translational Oncology, Quilmes National University, Bernal, Argentina.
Fundación Instituto Leloir, Consejo Nacional de Investigaciones Científicas y Técnicas (Instituto de Investigaciones Bioquímicas de Buenos Aires), Buenos Aires, Argentina.
Expert Opin Ther Targets. 2025 Jul;29(7):491-504. doi: 10.1080/14728222.2025.2537416. Epub 2025 Jul 27.
Paclitaxel (PTX) is a standard treatment for triple-negative breast cancer (TNBC), but its effectiveness is often compromised by toxicity at therapeutic doses. Dyskerin pseudouridine synthase 1 (DKC1), a telomerase subunit, is overexpressed in TNBC and associated with poor prognosis. This study investigates whether combining PTX with R1D2-10, a novel DKC1 inhibitor developed by our group, enhances cytotoxicity while reducing required PTX dosages.
assays were conducted using MDA-MB-231 and MDA-MB-468 TNBC cell lines, treated with R1D2-10, PTX or their combination. Cytotoxicity, drug synergy, clonogenic capacity, cell cycle distribution, apoptosis, and DNA damage markers were evaluated to assess efficacy and mechanism of action.
The combination demonstrated synergistic effects, showing dose-dependent cytotoxicity and achieving a Dose Reduction Index (DRI) exceeding 3. Furthermore, the treatment significantly reduced colony formation and induced a rise in cell cycle population, both at the G2/M and Sub-G1 phases. These effects are supported by increased apoptosis and gene expression markers for cell cycle arrest, without evidence of replication stress or DNA damage.
Combining R1D2-10 with PTX may provide an effective therapeutic strategy to reduce dose-related toxicity while enhancing chemotherapy effects in TNBC. Further, studies are needed to validate these findings.
紫杉醇（PTX）是三阴性乳腺癌（TNBC）的标准治疗药物，但其疗效常因治疗剂量下的毒性而受到影响。端粒酶亚基假尿苷合酶1（DKC1）在TNBC中过表达，且与预后不良相关。本研究调查将PTX与我们团队开发的新型DKC1抑制剂R1D2-10联合使用是否能增强细胞毒性，同时降低所需的PTX剂量。
使用MDA-MB-231和MDA-MB-468 TNBC细胞系进行实验，用R1D2-10、PTX或它们的组合进行处理。评估细胞毒性、药物协同作用、克隆形成能力、细胞周期分布、凋亡和DNA损伤标志物，以评估疗效和作用机制。
联合用药显示出协同效应，表现出剂量依赖性细胞毒性，剂量降低指数（DRI）超过3。此外，该治疗显著减少了集落形成，并导致细胞周期群体在G2/M期和亚G1期均增加。这些效应得到凋亡增加和细胞周期停滞基因表达标志物的支持，且无复制应激或DNA损伤的证据。
将R1D2-10与PTX联合使用可能提供一种有效的治疗策略，以降低与剂量相关的毒性，同时增强TNBC的化疗效果。此外，需要进一步研究来验证这些发现。
