title: Alterations in the mitochondrial responses to PENAO as a mechanism of resistance in ovarian cancer cells.
abstract: OBJECTIVE
  The purpose of this study was to test PENAO, a promising new organoarsenical that is in phase 1 testing in patients with solid tumours, on a range of ovarian cancer cell lines with different histotypes, and to understand the molecular basis of drug resistance exhibited by the endometrioid ovarian cancer cell line, SKOV-3.
  
  
  METHODS
  Proliferation arrest and cell death induced by PENAO in serous (OVCAR-3), endometrioid (SKOV-3, TOV112D), clear cell (TOV21G) and mucinous (EFO27) ovarian cancer cells in culture, and anti-tumour efficacy in a murine model of SKOV-3 and OVCAR-3 tumours, were measured. Cells were analysed for cell cycle arrest, cell death mechanisms, reactive oxygen species production, mitochondrial depolarisation, oxygen consumption and acid production.
  
  
  RESULTS
  PENAO demonstrated promising anti-proliferative activity on the most common (serous, endometrioid) as well as on rare (clear cell, mucinous) subtypes of ovarian cancer cell lines. No cross-resistance with platinum-based drugs was evident. Endometrioid SKOV-3 cells were, however, shown to be resistant to PENAO in vitro and in a xenograft mouse model. This resistance was due to an ability to cope with PENAO-induced oxidative stress, notably through heme oxygenase-1 induction, and a shift in metabolism towards glycolysis. The adaptive glycolytic shift in SKOV-3 was targeted using a mTORC1 inhibitor in combination with PENAO. This strategy was successful with the two drugs acting synergistically to inhibit cell proliferation and to induce cell death via apoptosis and autophagy.
  
  
  CONCLUSIONS
  Mitochondria/mTOR dual-targeting therapy may constitute a new approach for the treatment of recurrent/resistant forms of epithelial ovarian cancer.
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Decollogne
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Swapna
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Neuro Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Chung
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Luk
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Reichelle X
authors.initials: RX
authors.lastname: Yeo
authors.affiliation: Neuro Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Sheri
authors.initials: S
authors.lastname: Nixdorf
authors.affiliation: Ovarian Cancer Group, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: André
authors.initials: A
authors.lastname: Fedier
authors.affiliation: Ovarian Cancer Group, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: Viola
authors.initials: V
authors.lastname: Heinzelmann-Schwarz
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hogg
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: p.dilda@unsw.edu.au.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Dilda
mesh_terms: D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; C046652:phenylarsonous acid
keywords: Arsenic-based cancer drugs; Drug resistance; Metabolism; Mitochondria; Ovarian cancer; Oxidative stress; PENAO; mTOR signalling pathway