title: Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells.
abstract: The c-Myc gene encodes an oncoprotein transcription factor that is frequently upregulated in almost all cancer types and is the subject of intense investigation for management of cancer because of its pleiotropic effects controlling a spectrum of cellular functions. However, due of its nonenzymatic nature, development of suitable strategies to block its protein-protein or protein-DNA interaction is challenging. Thus, c-Myc has been recognized as an elusive molecular target for cancer control, and various approaches are in development to inhibit c-Myc transcriptional activity. We observed that wedelolactone (WDL), an anti-inflammatory botanical compound, severely downregulates the expression of c-Myc mRNA in prostate cancer cells. Moreover, WDL dramatically decreases the protein level, nuclear accumulation, DNA-binding, and transcriptional activities of c-Myc. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and is critical for maintaining their transformed phenotype. Interestingly, WDL was found to strongly affect the viability of Myc-activated prostate cancer cells and completely block their invasion as well as soft agar colony formation in vitro WDL was also found to downregulate c-Myc in vivo in nude mice xenografts. Moreover, WDL synergizes with enzalutamide to decrease the viability of androgen-sensitive prostate cancer cells via induction of apoptosis. These findings reveal a novel anticancer mechanism of the natural compound WDL, and suggest that the oncogenic function of c-Myc in prostate cancer cells can be effectively downregulated by WDL for the development of a new therapeutic strategy against Myc-driven prostate cancer. Mol Cancer Ther; 15(11); 2791-801. ©2016 AACR.
authors.affiliation: Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan.
authors.forename: Sivalokanathan
authors.initials: S
authors.lastname: Sarveswaran
authors.affiliation: Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan.
authors.forename: Ritisha
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan.
authors.forename: Rujul
authors.initials: R
authors.lastname: Parikh
authors.affiliation: Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan. jghosh1@hfhs.org.|Josephine Ford Cancer Center, Henry Ford Health System, Detroit, Michigan.
authors.forename: Jagadananda
authors.initials: J
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D003374:Coumarins; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; C051122:wedelolactone; D010669:Phenylthiohydantoin; C540278:enzalutamide