Tsinghua Berkeley Shenzhen Institute and the Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, 570006, India.
Cancer Lett. 2023 Nov 28;579:216443. doi: 10.1016/j.canlet.2023.216443. Epub 2023 Oct 17.
Even though tamoxifen has significantly improved the survival of estrogen receptor positive (ER+) mammary carcinoma (MC) patients, the development of drug resistance with consequent disease recurrence has limited its therapeutic efficacy. Trefoil factor-3 (TFF3) has been previously reported to mediate anti-estrogen resistance in ER+MC. Herein, the efficacy of a small molecule inhibitor of TFF3 (AMPC) in enhancing sensitivity and mitigating acquired resistance to tamoxifen in ER+MC cells was investigated. AMPC induced apoptosis of tamoxifen-sensitive and resistant ER+MC cells and significantly reduced cell survival in 2D and 3D culture in vitro. In addition, AMPC reduced cancer stem cell (CSC)-like behavior in ER+MC cells in a BCL2-dependent manner. Synergistic effects of AMPC and tamoxifen were demonstrated in ER+MC cells and AMPC was observed to improve tamoxifen efficacy in tamoxifen-sensitive cells and to re-sensitize cells to tamoxifen in tamoxifen-resistant ER+MC in vitro and in vivo. Additionally, tamoxifen-resistant ER+MC cells were concomitantly resistant to anthracycline, platinum and fluoropyrimidine drugs, but not to Taxanes. Taxane treatment of tamoxifen-sensitive and resistant ER+MC cells increased TFF3 expression indicating a combination vulnerability for tamoxifen-resistant ER+MC cells. Taxanes increased CSC-like behavior of tamoxifen-sensitive and resistant ER+MC cells which was reduced by AMPC treatment. Taxanes synergized with AMPC to promote apoptosis and reduce CSC-like behavior in vitro and in vivo. Hence, AMPC restored the sensitivity of tamoxifen and enhanced the efficacy of Taxanes in tamoxifen-resistant ER+MC. In conclusion, pharmacological inhibition of TFF3 may serve as an effective combinatorial therapeutic strategy for the treatment of tamoxifen-resistant ER+MC.
尽管他莫昔芬显著提高了雌激素受体阳性（ER+）乳腺癌（MC）患者的生存率，但耐药性的发展导致疾病复发，限制了其治疗效果。三叶因子 3（TFF3）先前被报道可介导 ER+MC 中的抗雌激素耐药性。在此，研究了 TFF3 的小分子抑制剂（AMPC）在增强 ER+MC 细胞对他莫昔芬的敏感性和减轻获得性耐药方面的疗效。AMPC 诱导他莫昔芬敏感和耐药的 ER+MC 细胞凋亡，并显著降低体外 2D 和 3D 培养中的细胞存活率。此外，AMPC 以 BCL2 依赖的方式降低 ER+MC 细胞中的癌症干细胞（CSC）样行为。在 ER+MC 细胞中证明了 AMPC 和他莫昔芬的协同作用，并且观察到 AMPC 提高了他莫昔芬在他莫昔芬敏感细胞中的疗效，并在体外和体内使他莫昔芬耐药的 ER+MC 细胞重新对他莫昔芬敏感。此外，他莫昔芬耐药的 ER+MC 细胞同时对蒽环类、铂类和氟嘧啶类药物耐药，但对紫杉烷类药物不耐药。紫杉烷类药物治疗他莫昔芬敏感和耐药的 ER+MC 细胞增加了 TFF3 的表达，表明他莫昔芬耐药的 ER+MC 细胞存在组合脆弱性。AMPC 处理降低了紫杉烷类药物敏感和耐药的 ER+MC 细胞的 CSC 样行为。紫杉烷类药物与 AMPC 协同作用，在体外和体内促进凋亡并降低 CSC 样行为。因此，AMPC 恢复了他莫昔芬的敏感性，并增强了紫杉烷类药物在他莫昔芬耐药的 ER+MC 中的疗效。总之，TFF3 的药理抑制可能成为治疗他莫昔芬耐药的 ER+MC 的有效联合治疗策略。
