title: Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy.
abstract: Ovarian cancer is one of the most important malignancies, and the origin, detection, and pathogenesis of epithelial ovarian cancer remain elusive. Although many cancer drugs have been developed to dramatically reduce the size of tumors, most cancers eventually relapse, posing a critical problem to overcome. Hence, it is necessary to identify possible alternative therapeutic approaches to reduce the mortality rate of this devastating disease. To identify alternative approaches, we first synthesized silver nanoparticles (AgNPs) using a novel bacterium called Bacillus clausii. The synthesized AgNPs were homogenous and spherical in shape, with an average size of 16-20 nm, which are known to cause cytotoxicity in various types of human cancer cells, whereas salinomycin (Sal) is able to kill cancer stem cells. Therefore, we selected both Sal and AgNPs to study their combined effect on apoptosis and autophagy in ovarian cancer cells. The cells treated with either Sal or AgNPs showed a dose-dependent effect with inhibitory concentration (IC)-50 values of 6.0 µM and 8 µg/mL for Sal and AgNPs, respectively. To determine the combination effect, we measured the IC25 values of both Sal and AgNPs (3.0 µM and 4 µg/mL), which showed a more dramatic inhibitory effect on cell viability and cell morphology than either Sal or AgNPs alone. The combination of Sal and AgNPs had more pronounced effect on cytotoxicity and expression of apoptotic genes and also significantly induced the accumulation of autophagolysosomes, which was associated with mitochondrial dysfunction and loss of cell viability. Our data show a strong synergistic interaction between Sal and AgNPs in tested cancer cells. The combination treatment increased the therapeutic potential and demonstrated the relevant targeted therapy for the treatment of ovarian cancer. Furthermore, we provide, for the first time, a mode of action for Sal and AgNPs in ovarian cancer cells: enhanced apoptosis and autophagy.
authors.affiliation: College of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, People's Republic of China.
authors.forename: Xi-Feng
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Department of Stem Cell and Regenerative Biology, Konkuk University, Seoul, South Korea.
authors.forename: Sangiliyandi
authors.initials: S
authors.lastname: Gurunathan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects*; D001407:Bacillus / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D011714:Pyrans / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D012834:Silver / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D053148:Caspase 3; D011714:Pyrans; D012834:Silver; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: apoptosis; autophagy; caspase activity; cell viability; ovarian cancer; salinomycin; silver nanoparticles