Alpinumisoflavone Disrupts Endoplasmic Reticulum and Mitochondria Leading to Apoptosis in Human Ovarian Cancer

Abstract

Alpinumisoflavone is a prenylated isoflavonoid derived from the Cudrania tricuspidate fruit and Genista pichisermolliana. Alpinumisoflavone has anticancer properties in a variety of cancer cells, including colorectal, esophageal, renal and hepatocellular carcinoma. However, its mechanisms and effects in ovarian cancer remain unexplored. Our findings indicate that alpinumisoflavone triggers anti-proliferation in 2D- and 3D-cultured human ovarian cancer (ES2 and OV90) cells, including a reduction in the proliferating cell nuclear antigen expression and sub-G1 phase arrest of the cell cycle. Both alpinumisoflavone-treated ES2 and OV90 cells exhibited an augmentation in late apoptotic cells and the depolarization of mitochondrial membrane potential (MMP). We also observed a decrease in respiratory chain activity in ovarian cancer cells, owing to lower energy output by the alpinumisoflavone. In addition, combining cisplatin (a chemotherapeutic drug used in several malignancies) with alpinumisoflavone boosted apoptosis in ES2 and OV90 cells via a reduction in cell proliferation, induction of late apoptotic cells, and depolarization of MMP. Furthermore, alpinumisoflavone also regulated the PI3K/AKT, MAPK and endoplasmic reticulum (ER) stress regulatory signaling pathways, leading to cell death in both ES2 and OV90 cells. In general, our findings verified that alpinumisoflavone inhibited ovarian cancer cell growth via mitochondrial malfunction.

Alpinumisoflavone Impairs Mitochondrial Respiration via Oxidative Stress and MAPK/PI3K Regulation in Hepatocellular Carcinoma Cells

“…Mitochondria are closely involved in cell survival, ATP production, maintenance of calcium homeostasis, and regulation of apoptosis [ 37 ]. Furthermore, it has been demonstrated that alpinumisoflavone can induce apoptosis via depolarization of the MMP in human ovarian cancer cells, which is consistent with our results [ 17 ]. Maintaining the polarization of the MMP is crucial for mitochondria, and the liver is a major metabolic organ supplying energy to our bodies [ 38 ].…”

“…Immunoblots were captured using the Image Lab software. Each total protein and alpha-tubulin (TUBA) were utilized as a loading control for normalization [ 17 ].…”

“…Alpinumisoflavone could further prevent the progression of osteoporosis and improve the cholesterol profile in blood [ 14 ], as well as enhance the sensitivity to apoptosis in radioresistant esophageal squamous cell carcinoma [ 15 ]. In addition, several studies have proven that alpinumisoflavone could induce apoptosis in kidney cancer via miRNA regulation and in human ovarian cancer via mitochondrial dysfunction [ 16 , 17 ]. However, few studies have shown the anti-cancer effects of alpinumisoflavone as a liver cancer treatment.…”

Alpinumisoflavone Activates Disruption of Calcium Homeostasis, Mitochondria and Autophagosome to Suppress Development of Endometriosis

“…Alpinumisoflavone, one of the natural antioxidants, is known as a prenylated isoflavonoid, which is extracted from Cudrania tricuspidate fruit and Genista pichisermolliana. The physiological effects of alpinumisoflavone, such as in the inhibition of progression of tumorigenesis, have been widely reported in several previous studies [5,6]. Representatively, alpinumisoflavone induces NLRP3 inflammasome-meditated pyroptosis in hepatocellular carcinoma [7].…”

The role of NLRP3 inflammasome in hepatocellular carcinoma

“…In the above study, the relationship between autophagy and NLRP3 inflammasome in HCC cells deserves further study in the future. In addition, it has been reported that AIF can promote the apoptosis of cancer cells ( Han et al, 2016 ; Hong et al, 2022 ). Therefore, whether AIF can induce apoptosis of HCC cells through NLRP3 inflammasome remains to be clarified.…”