Azelnidipine

Zhao L, et al. Molecular Therapy - Oncolytics, 2022, 27, 61-72.

Azelnidipine, a clinically approved calcium channel blocker, was evaluated for its antitumor potential against esophageal squamous cell carcinoma (ESCC). In vitro, ESCC cell lines were treated with azelnidipine, and proliferation was assessed via cell viability assays. Pull-down and cellular thermal shift assays identified MEK1/2 as direct molecular targets, while in vitro kinase assays confirmed suppression of MEK1/2 activity. Consequent ERK1/2 hypophosphorylation led to reduced Cyclin D1/CDK6 levels. In vivo efficacy was demonstrated using patient-derived xenograft models, where azelnidipine administration inhibited tumor growth comparably to trametinib. This study establishes azelnidipine as a dual MEK1/2 inhibitor with direct experimental application in ESCC therapy.

Huang T, et al. Nano Today, 2022, 47, 101682.

Azelnidipine (AZL) is a calcium channel blocker with potent inhibitory effects on endometrial cancer (EC) cells.. AZL was encapsulated in liposomal nanoparticles (NP@AZL) to enhance solubility and tumor targeting. NP@AZL was evaluated in vitro across four EC cell lines and patient-derived cells, demonstrating superior cytotoxicity compared to free AZL. Mechanistically, NP@AZL disrupted intracellular calcium homeostasis, induced endoplasmic reticulum (ER) stress, and activated the CHOP-TRIB3 apoptotic pathway. Combination treatment with medroxyprogesterone acetate (MPA) amplified ER stress, upregulated pro-apoptotic genes, and inhibited DNA replication, resulting in enhanced cell death. In EC-bearing mouse models, intravenous NP@AZL achieved tumor accumulation and synergized with MPA to significantly suppress tumor growth, highlighting its potential as a targeted experimental therapy for EC.

Nasu F, et al. Life Sciences, 2021, 269, 119043.

This study investigated the effects of azelnidipine, a third-generation dihydropyridine calcium channel blocker, on Cav1.2 protein expression. HEK293 cells and rat pulmonary artery smooth muscle cells were employed to evaluate the modulation of L-type Cav1.2 channels. Immunocytochemistry assessed surface expression of the Cav1.2α1c subunit, while Western blotting quantified total Cav1.2α1c and Cavβ2c proteins. Azelnidipine treatment markedly reduced surface and total Cav1.2α1c levels, a mechanism not observed with amlodipine or nicardipine. Proteasome inhibition rescued Cav1.2α1c reduction, indicating post-translational regulation. Experiments with a dynamin inhibitor and early endosome markers suggested the effect was independent of internalization. These findings highlight azelnidipine's unique experimental application in downregulating Cav1.2 channels, providing mechanistic insight into its prolonged hypotensive action.