文章：

通过抑制DNA修复，黄酮苷XGAc在三阴性乳腺癌、卵巢癌和胰腺癌中的抗肿瘤活性

Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair

原文发布日期：6 December 2023

DOI: 10.3390/cancers15245718

类型: Article

开放获取: 是

英文摘要：

Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. The xanthonoside XGAc was previously described as a potent inhibitor of cancer cell growth. Herein, we explored its antitumor activity against triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC) cells as a single agent and in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. We demonstrated that XGAc inhibited the growth of TNBC, ovarian and PDAC cells by inducing cell cycle arrest and apoptosis. XGAc also induced genotoxicity, inhibiting the expression of DNA repair proteins particularly involved in homologous recombination, including BRCA1, BRCA2 and RAD51. Moreover, it displayed potent synergistic effects with olaparib in TNBC, ovarian cancer and PDAC cells. Importantly, this growth inhibitory activity of XGAc was further reinforced in a TNBC spheroid model and in patient-derived ovarian cancer cells. Also, drug-resistant cancer cells showed no cross-resistance to XGAc. Additionally, the ability of XGAc to prevent cancer cell migration was evidenced in TNBC, ovarian cancer and PDAC cells. Altogether, these results highlight the great potential of acetylated xanthonosides such as XGAc as promising anticancer agents against hard-to-treat cancers.

摘要翻译： 

DNA损伤反应的失调可能通过驱动细胞死亡，增强癌细胞对DNA靶向药物的敏感性。事实上，抑制DNA修复通路被认为是一种有前景的抗癌治疗策略，尤其在与标准治疗药物联用时效果显著。先前研究表明，黄酮苷衍生物XGAc是一种有效的癌细胞生长抑制剂。本研究探讨了XGAc作为单药及与聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）奥拉帕利联用时，对三阴性乳腺癌（TNBC）、卵巢癌和胰腺导管腺癌（PDAC）细胞的抗肿瘤活性。实验证明，XGAc通过诱导细胞周期阻滞和细胞凋亡，抑制TNBC、卵巢癌和PDAC细胞的生长。XGAc还能诱导基因毒性，抑制同源重组修复相关蛋白（包括BRCA1、BRCA2和RAD51）的表达。此外，XGAc与奥拉帕利在TNBC、卵巢癌和PDAC细胞中显示出显著的协同效应。重要的是，XGAc的这种生长抑制活性在TNBC球状体模型和患者来源的卵巢癌细胞中得到进一步验证。同时，耐药癌细胞对XGAc未表现出交叉耐药性。此外，XGAc在TNBC、卵巢癌和PDAC细胞中均显示出抑制癌细胞迁移的能力。综上所述，这些结果凸显了乙酰化黄酮苷类化合物（如XGAc）作为治疗难治性癌症的潜在抗癌药物的巨大前景。

原文链接：

Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair