Azelnidipine nanoparticles break calcium homeostasis and induce severe ER stress combined with medroxyprogesterone acetate for endometrial cancer therapy. (December 2022)

• Record Type: Journal Article
• Authors: Huang, Ting; Zhou, Jingyi; Zhang, Lingpu; Yang, Xiao; Cheng, Yuan; Yin, Shenyi; Wang, Jiaqi; Shen, Boqiang; Feng, Xuan; Li, Xingchen; Dong, Yangyang; Xiao, Haihua; Wang, Jianliu
• Is Part Of: Nano today. Volume 47(2022)
• Publication Date: 2022-12
• Subjects: Endometrial cancer -- Azelnidipine -- Nanoparticles -- MPA -- Calcium homeostasis -- ER stress; EC Endometrial cancer -- ER Endoplasmic reticulum -- CCB Calcium channel blocker -- AZL Azelnidipine -- PDC Patient-derived cell -- MPA Medroxyprogesterone acetate -- CHOP C/EBP homologous protein -- TRIB3 Tibbles pseudo-kinase 3 -- ATF4 Activating transcription factor 4; Nanotechnology -- Periodicals; Nanosciences -- Périodiques; 620.505
• DOI: 10.1016/j.nantod.2022.101682
• Languages: English
• ISSNs: 1748-0132

Abstract

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. Graphical Abstract: ga1 Highlights: High calcium levels are associated with EC progression. AZL was screened out of 19 FDA-approved CCBs for its outstanding anticancer effects in EC cells. NP@AZL was prepared to functionalize the liposomes for targeted delivery. NP@AZL triggered ER stress, activated CHOP-TRIB3 pathway and promoted cell apoptosis. NP@AZL synergized with MPA resulted in severe ER stress and promoted EC cell death.