Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA, United States of America; Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, United States of America.
Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA, United States of America.
Fitoterapia. 2022 Jul;160:105203. doi: 10.1016/j.fitote.2022.105203. Epub 2022 Apr 27.
The Petiveria alliacea L. (P. alliacea) plant is traditionally used in folklore medicine throughout tropical regions of the world to treat arthritis, asthma, and cancer. Dibenzyl trisulfide (DTS) is one of the active ingredients within the P. alliacea plant. Triple-negative breast cancer (TNBC) is associated with a poor prognosis, particularly among women of West African ancestry, due in part to limited effective therapy. Though potent anticancer actions of DTS have been reported in a TNBC cell line, the mechanism of DTS-mediated cytotoxicity and cell death remains ill-defined. In the current study, we show that DTS exhibits cytotoxicity in a panel of triple-negative breast cancer (TNBC) cells derived from patients of European and West African ancestry. We found that DTS inhibits proliferation and migration of CRL-2335 cells derived from a patient of West African ancestry. DTS induces the expression of pro-apoptotic genes BAK1, GADD45a, and LTA in CRL2335 cells though it primarily promotes caspase-independent CRL-2335 cell death. DTS also promotes destabilization of the lysosomal membrane resulting in cathepsin B release in CRL-2335 cells. Finally, Kaplan-Meier survival curves reveal that higher expression of BAK1 and LTA in tumors from patients with TNBC is associated with longer relapse-free survival. Collectively, our data suggest that DTS confers promising antitumor efficacy in TNBC, in part, via lysosomal-mediated, caspase-independent cell death to warrant furthering its development as an anticancer agent.
佩蒂弗尼亚全草（P. alliacea）植物在世界热带地区的传统民间医学中被用于治疗关节炎、哮喘和癌症。二苄基三硫化物（DTS）是佩蒂弗尼亚全草植物中的一种活性成分。三阴性乳腺癌（TNBC）与预后不良有关，特别是在具有西非血统的女性中，部分原因是有效治疗方法有限。尽管 DTS 在 TNBC 细胞系中具有强大的抗癌作用，但 DTS 介导的细胞毒性和细胞死亡的机制仍不清楚。在本研究中，我们表明 DTS 对源自欧洲和西非血统的患者的一组三阴性乳腺癌（TNBC）细胞具有细胞毒性。我们发现 DTS 抑制了源自西非血统患者的 CRL-2335 细胞的增殖和迁移。DTS 通过诱导 BAK1、GADD45a 和 LTA 等促凋亡基因的表达来诱导 CRL2335 细胞的凋亡，但主要促进 caspase 非依赖性 CRL-2335 细胞死亡。DTS 还促进溶酶体膜的不稳定，导致 CRL-2335 细胞中组织蛋白酶 B 的释放。最后，Kaplan-Meier 生存曲线显示，TNBC 患者肿瘤中 BAK1 和 LTA 的高表达与无复发生存时间延长相关。总之，我们的数据表明，DTS 在 TNBC 中具有有前途的抗肿瘤疗效，部分原因是通过溶酶体介导的 caspase 非依赖性细胞死亡来保证其作为抗癌剂的进一步发展。
