lacidipine and benidipine

Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry.

Topics: Amlodipine; Animals; Antioxidants; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cattle; Dihydropyridines; Epithelial Cells; Humans; Hydrogen; Lipoproteins, LDL; Mice; Microsomes; Mitochondria; Niacinamide; Nifedipine; Nitrobenzenes; Oxidants; Oxidative Stress; Piperazines

Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.

Topics: Animals; Antihypertensive Agents; Apoptosis; Calcium Channel Blockers; Calcium Channels; Carcinoma, Ovarian Epithelial; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Dihydropyridines; Drug Repositioning; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Neoplastic Stem Cells; Nitrobenzenes; Ovarian Neoplasms; Paclitaxel; Piperazines; Signal Transduction; Tumor Microenvironment