Sinularin, an Anti-Cancer Agent Causing Mitochondria-Modulated Apoptosis and Cytoskeleton Disruption in Human Hepatocellular Carcinoma

Abstract

Liver cancer remains a leading cause of death, despite advances in anti-cancer therapies. To develop novel drugs, natural products are being considered as a good source for exploration. In this study, a natural product isolated from a soft coral was applied to evaluate its anti-cancer activities in hepatocellular carcinoma SK-HEP-1 cells. Sinularin was determined to have half-maximal inhibitory concentration (IC50) values of ~10 μM after 24, 48, and 72 h. The TUNEL assay and annexin V/PI staining results showed that sinularin induced DNA fragmentation and apoptosis, respectively. An investigation at the molecular level demonstrated that the expression levels of cleaved caspases 3/9 were significantly elevated at 10 μM sinularin. Mitochondrial and intracellular reactive oxygen species (ROS) levels were significantly increased following sinularin treatment, which also affected the mitochondrial membrane potential. In addition, it significantly lowered the mitochondrial respiration parameters and extracellular acidification rates at 10 μM. Further investigation showed that sinularin significantly attenuated wound healing, cell migration, and potential colony formation at 10 μM. Fluorescence microscopic observations showed that the distribution of F-actin filaments was significantly altered at 10 μM sinularin. Supported by Western blot analyses, the expression levels of AKT, p-ERK (extracellular-signal-related kinase), vimentin and VEGF were significantly down-regulated, whereas p-p38, pJNK and E-cadherin were significantly increased. Overall, at the IC50 concentration, sinularin was able to significantly affect SK-HEP-1 cells.

Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species

“…The following procedures were conducted as described in the literature [ 36 , 37 ]. Intracellular ROS were determined by hydrogen peroxide (H 2 O 2 ) level using a chemical probe CM-H 2 DCFDA.…”

“…The following procedures were conducted as described in the literature [ 36 , 37 ]. Mitochondrial superoxide (O2 •− ) level was analyzed by cell-permeable MitoSOX TM Red (Molecular Probes, Inc), a redox-sensitive dye believed to specifically target mitochondrial matrix, and red fluorescence is emitted upon oxidation.…”

“…The following procedures were conducted as described in the literature [ 37 ]. A fluorescent dye, JC-1, was used for detecting mitochondrial membrane depolarization.…”

Cytotoxic Compounds from Alcyoniidae: An Overview of the Last 30 Years

“…Sinugrandisterol A (190) showed cytotoxicity against the proliferation of HepG2 and MDA-MB-231 cells ((IC 50 of 9.1 and 9.2 µg/mL, respectively), while sinugrandisterol B (191) was found to be cytotoxic exclusively to HepG2 cancer cell line with (IC 50 of 6.8 µg/mL. Two new xeniaphyllane-derived metabolites, gibberosins K (192) and L (193), extracted from S. gibberosa by Chen et al [97], exhibited activity against A-549 (human lung carcinoma), HepG2 (human hepatocellular carcinoma), and MDA-MB-231 (human breast carcinoma) cell lines with (IC 50 values ranging from 5.5 to 14.5 mg/mL.…”

“…The studies conducted by Ma et al [192] revealed that sinularin (205) induced G2/M arrest and induced apoptosis as well as activation of MAPKs and repression of PI3K/AKT pathways, which are dependent on ROS generation, in human renal cancer (786-O) cells. Recently, Ko et al [193] have thoroughly investigated the effect of sinularin (205) on human hepatocellular cancer (SK-HEP-1) cells and found that wound healing, cell migration, and potential colony formation were attenuated as well as DNA fragmentation and apoptosis were induced and mitochondrial and intracellular reactive oxygen species (ROS) levels were significantly increased following sinularin treatment, which also decreased the mitochondrial membrane potential and caused cytoskeleton disruption [194].…”