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

Abstract

Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and ovarian cancers, but its therapeutic effects on hepatocellular carcinoma (HCC) have not yet been demonstrated. We investigated the anti-cancer effects of alpinumisoflavone on HCC using human liver cancer cell lines, Hep3B and Huh7. Our results confirmed that alpinumisoflavone inhibited viability and regulated the MAPK/PI3K pathway in Hep3B and Huh7 cells. We also verified that alpinumisoflavone can depolarize the mitochondrial membrane potential and suppress the mitochondrial respiration in HCC cells. Moreover, we confirmed the dysregulation of the mitochondrial complexes I, III, and V involving mitochondrial oxidative phosphorylation at the mRNA level and the accumulation of calcium ions in the mitochondrial matrix. Lastly, we demonstrated that alpinumisoflavone induced mitochondria-mediated apoptosis via regulation of the Bcl-xL and BAK proteins. This study elucidates the anti-cancer effects of alpinumisoflavone on HCC.

Effect and Mechanism of Schizandrin A in the Treatment of Liver Cancer Using Network Pharmacology, Molecular Docking, and Target Validation

“…The occurrence and development of liver cancer are closely related to inflammation and oxidative stress, which are also common ways of anti-liver cancer therapy. 24 As the active monomer component of TCM, SA has certain anti-inflammatory and antioxidant stress effects, and therefore, its antitumor possibility has gradually become a research focus. 25,26 The results of network pharmacology in this research suggest that SA may relieve the inflammatory state of HepG2 cells by regulating TNF-α, IL-6, IL-1β, IFN, IL-10, IFN, and other inflammatory factors, so as to play a certain therapeutic effect.…”

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].…”

“…Also, it suppresses the lesion size of tumor and invasive properties in clear-cell renal cell carcinoma by regulating RLIP76-miR-101 signaling pathways [8]. In a previous study, we identified that alpinumisoflavone disrupted mitochondrial energetics and redox homeostasis, leading to the death of liver cancer cells [5]. Although alpinumisoflavone, which belongs to a class of isoflavonoids with diverse efficacy, has been proven effective in malignant tumors, such as hepatocellular carcinoma, clear-cell renal cell carcinoma and ovarian cancer, via induction of oxidative stress, a study to identify mechanisms related to endometriosis, a benign reproductive disease, has not been reported yet.…”