title: Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells.
abstract: Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibition with HCI-2509 in advanced stages of prostate cancer.
  
  
  
  Cell survival, colony formation, histone methylation, c-MYC level, c-MYC expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with HCI-2509. In vitro combination studies, using HCI-2509 and docetaxel, were performed to assess the synergy. Cell survival, colony formation, histone methylation and c-myc levels were studied in docetaxel-resistant prostate cancer cells treated with HCI-2509.
  
  
  
  HCI-2509 is cytotoxic and inhibits colony formation in castration-resistant prostate cancer cells. HCI-2509 treatment causes a dose-dependent increase in H3K9me2 (histone H3lysine 9) levels, a decrease in c-MYC protein, inhibition of c-MYC expression and accumulation in the G0/G1 phase of the cell cycle in these cells. PC3 xenografts in mice have a significant reduction in tumor burden upon treatment with HCI-2509 with no associated myelotoxicity or weight loss. More synergy is noted at sub-IC50(half-maximal inhibitory concentration) doses of docetaxel and HCI-2509 in PC3 cells than in DU145 cells. HCI-2509 has growth-inhibitory efficacy and decreases the c-myc level in docetaxel-resistant prostate cancer cells.
  
  
  
  LSD1 inhibition with HCI-2509 decreases the c-MYC level in poorly differentiated prostate cancer cell lines and has a therapeutic potential in castration- and docetaxel-resistant prostate cancer.
authors.affiliation: GU Medical Oncology, Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.affiliation: GU Medical Oncology, Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Weston
authors.affiliation: GU Medical Oncology, Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bearrs
authors.affiliation: GU Medical Oncology, Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Thode
authors.affiliation: GU Medical Oncology, Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Neiss
authors.affiliation: Beta Cat Pharmaceuticals, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Soldi
authors.affiliation: GU Medical Oncology, Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D008024:Ligands; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D056466:Histone Demethylases; C495195:KDM1A protein, human