title: Combined treatment targeting HIF-1α and Stat3 is a potent strategy for prostate cancer therapy.
abstract: BACKGROUND
  The Stat3 pathway and the hypoxia-sensing pathway are both up-regulated in prostate cancer. Stat3 is a specific regulator of pro-carcinogenic inflammation and represents a promising therapeutic target. Hypoxia-inducible factor-1 (HIF-1)α, which mediates the cellular response to hypoxia, has been demonstrated to be over-expressed in many human cancers and is associated with poor prognosis and treatment failure in clinic. To develop a potent strategy to increase therapeutic efficacy and reduce drug resistance in prostate cancer therapy, we combined two anti-cancer agents: T40214 (a p-Stat3 inhibitor) and JG244 (a HIF-1α inhibitor) together to treat nude mice bearing human prostate tumor (DU145) and immunocompetent mice (C57BL/6) bearing murine prostate tumor (TRAMP-C2).
  
  
  METHODS
  We employed in vitro and in vivo assays, including Western blots, cell cycle analysis, immunohistochemistry, TUNEL and xenograft models to determine the drug efficacy and mechanism of combination treatment of T40214 and JG244.
  
  
  RESULTS
  We found that compared to treatment by T40214 or JG244 alone, the combination treatment using T40214 and JG244 together significantly suppressed growth of human or murine prostate tumors. Also, compared with apoptotic cells induced by T40214 or JG244 alone, the combined treatment greatly increased apoptosis in DU145 (P < 0.006) and TRAMP-C2 tumors (P < 0.008).
  
  
  CONCLUSIONS
  Our results suggested that combination treatment including a HIF-1α/2α inhibitor not only has therapeutic efficacy in targeting HIF-1α/2α, but also could reduce the hypoxia-induced drug resistance to other therapies (e.g., T40214) and enhance drug efficacy. This approach could make prostate cancer treatments more effective.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Kavitha Ramasamy
authors.initials: KR
authors.lastname: Reddy
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guan
authors.forename: Guoting
authors.initials: G
authors.lastname: Qin
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Naijie
authors.initials: N
authors.lastname: Jing
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D009841:Oligonucleotides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C510005:GQ-ODN T40214; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C568499:ODN JG244; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse