title: Englerin a selectively induces necrosis in human renal cancer cells.
abstract: The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells. This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages. However, little is known about englerin A's mode of action in targeting specifically renal cancer cells. Our study is the first to investigate the biological mechanism of englerin A action in detail. We report that englerin A is specific for renal tumor cells and does not affect normal kidney cells. We find that englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells. We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm. As the first study to analyze the biological effects of englerin A, our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug. It also provides a context in which to identify the specific target or targets of englerin A in renal cancer cells.
authors.affiliation: Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Sulzmaier
authors.forename: Zhenwu
authors.initials: Z
authors.lastname: Li
authors.forename: Mika L
authors.initials: ML
authors.lastname: Nakashige
authors.forename: David M
authors.initials: DM
authors.lastname: Fash
authors.forename: William J
authors.initials: WJ
authors.lastname: Chain
authors.forename: Joe W
authors.initials: JW
authors.lastname: Ramos
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D009336:Necrosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D045789:Sesquiterpenes, Guaiane / Q000737:chemistry / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D045789:Sesquiterpenes, Guaiane; C534971:englerin A; D002738:Chloroquine; D019311:Staurosporine; D002118:Calcium