Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
Department of Pharmacy, The Seventh People's Hospital of Wenzhou, Wenzhou, 325006, Zhejiang, People's Republic of China.
Med Oncol. 2021 Apr 21;38(6):59. doi: 10.1007/s12032-021-01505-x.
Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide. High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this influences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in HO. The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and HO exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells, but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and HO activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and HO combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that HO enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.
癌症是威胁人类健康的疾病之一，也是全球死亡的主要原因之一。与体内正常组织相比，癌症组织中观察到高水平的活性氧（ROS），但目前尚不清楚这如何影响化疗药物的作用。阳离子卟啉 5,10,15,20-四（N-甲基-4-吡啶基）卟啉（TMPyP4）是一种用于光动力疗法（PDT）的光敏剂和一种用于治疗端粒酶阳性癌症的端粒酶抑制剂。在这里，我们研究了 TMPyP4 在 HO 培养的 A549 和 PANC 细胞中的抗癌活性。结果表明，与 TMPyP4 单独相比，TMPyP4 和 HO 的组合对 A549 和 PANC 细胞的细胞活力和集落形成抑制以及细胞凋亡表现出敏化作用，但对人正常 MIHA 细胞没有影响。从机制上讲，TMPyP4 和 HO 的组合在 A549 和 PANC 细胞中激活高 ROS 和线粒体膜电位，导致强烈的 DNA 损伤和 DNA 损伤反应。因此，与 TMPyP4 单独相比，TMPyP4 和 HO 联合处理上调了 A549 和 PANC 细胞中 BAX、cleaved caspase 3 和 p-JNK 的表达，并下调了 Bcl-2 的表达。综上所述，这些数据表明 HO 增强了 TMPyP4 介导的 ROS 依赖性 DNA 损伤和相关凋亡蛋白调节的抗癌活性，揭示了高 ROS 肿瘤微环境在化疗药物作用中起着重要作用。
