Azelnidipine nanoparticles break calcium homeostasis and induce severe ER stress combined with medroxyprogesterone acetate for endometrial cancer therapy

Abstract

Calcium homeostasis plays a crucial role in many cellular processes. The disruption of calcium homeostasis triggers endoplasmic reticulum (ER) stress and contributes to cell death, thus representing a potential target for cancer therapy. Calcium channel blockers (CCBs) are the first-line calcium ion modulators for hypertension but with anti-tumor activities. However, their effects on the cardiovascular system and the poor water solubility hampered their widespread use as anticancer drugs. Herein, we screened out Azelnidipine (AZL) of 19 FDA-approved CCBs, and found AZL had the best tumor inhibitory effect on endometrial cancer (EC) cells. Subsequently, liposomes are adopted to encapsulate AZL to form nanoparticles (NP@AZL) for drug delivery. NP@AZL showed better inhibitory effects on four EC cell lines and advanced patient-derived cells (PDCs) than AZL alone in vitro. Inside a cancer model of EC-bearing mice, NP@AZL was able to accumulate in the tumor, and combine with medroxyprogesterone acetate (MPA) to significantly inhibit tumor growth. Mechanistic study by transcriptome revealed that NP@AZL combined with MPA resulted in severe ER stress, and upregulation of pro-apoptotic genes, ultimately inhibiting DNA replication to promote cell death. Therefore, the strategy of disrupting calcium homeostasis and activating severe ER stress through combination therapy may serve as a paradigm for future EC treatment.