Bergel Ceyda Colakoglu, Eryilmaz Isil Ezgi, Bulut Ebrucan, Balaban Rumeysa Fatma, Egeli Unal, Cecener Gulsah
Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey.
Anticancer Agents Med Chem. 2025;25(9):610-619. doi: 10.2174/0118715206336754241015062614.
Prostate cancer (PC) affects millions of men, causing high mortality rates. Despite the treatment approaches, the options for metastatic castration-resistant prostate cancer (mCRPC), a lethal form of advanced PC, are still limited. Cabazitaxel (Cbx) is the last taxane-derived chemotherapeutic approved for Docetaxel- resistant mCRPC patients. However, its effects are limited due to the activation of several pathways. Therefore, new approaches are needed to increase the efficacy of Cbx. Usnic acid (UA) is a natural product with wellknown anti-tumorigenic and synergistic effects with various chemotherapeutics. Although the cytotoxicity of UA and Cbx has been evaluated on mCRPC cells, the anti-tumorigenic effect of UA combination with any taxane has not been investigated yet. Thus, we aimed to evaluate the possible synergistic effect of Cbx+UA in mCRPC cells.
Cell viability and apoptosis were analyzed using WST-1 and Annexin-V. Morphological changes were visualized by fluorescent staining. Finally, cell cycle, mitochondrial health, and ROS levels were determined.
Based on WST-1 results, 25 μM UA exhibited significant additive and synergistic effects with the use of Cbx. Annexin V and cell cycle results showed that UA significantly enhanced the Cbx efficacy at increasing doses compared to using only Cbx (**p<0.01). Moreover, combined treatment significantly increased ROS levels and mitochondrial membrane depolarization compared with Cbx alone (**p<0.01).
Thus, the results suggest that UA increased the anti-tumorigenic effects of Cbx on mCRPC cells by increasing apoptosis, causing an increase in intracellular ROS and disrupting mitochondrial health. Consequently, combining UA and Cbx offers a new combined therapeutic strategy for mCRPC treatment.
前列腺癌（PC）影响着数百万男性，导致高死亡率。尽管有多种治疗方法，但转移性去势抵抗性前列腺癌（mCRPC），一种晚期PC的致命形式，其治疗选择仍然有限。卡巴他赛（Cbx）是最后一种被批准用于多西他赛耐药mCRPC患者的紫杉烷类化疗药物。然而，由于多种途径的激活，其效果有限。因此，需要新的方法来提高Cbx的疗效。松萝酸（UA）是一种天然产物，具有众所周知的抗肿瘤作用以及与多种化疗药物的协同作用。尽管已经评估了UA和Cbx对mCRPC细胞的细胞毒性，但尚未研究UA与任何紫杉烷联合使用的抗肿瘤作用。因此，我们旨在评估Cbx + UA在mCRPC细胞中可能的协同作用。
使用WST-1和膜联蛋白V分析细胞活力和凋亡。通过荧光染色观察形态学变化。最后，测定细胞周期、线粒体健康状况和活性氧水平。
基于WST-1结果，25 μM的UA与Cbx联合使用时表现出显著的相加和协同作用。膜联蛋白V和细胞周期结果表明，与仅使用Cbx相比，UA在增加剂量时显著增强了Cbx的疗效（**p<0.01）。此外，联合治疗与单独使用Cbx相比，显著提高了活性氧水平和线粒体膜去极化（**p<0.01）。
因此，结果表明UA通过增加凋亡、导致细胞内活性氧增加和破坏线粒体健康，增强了Cbx对mCRPC细胞的抗肿瘤作用。因此，联合使用UA和Cbx为mCRPC治疗提供了一种新的联合治疗策略。
