title: The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells.
abstract: OBJECTIVE
  Retinoids are important modulators of cell growth, differentiation, and proliferation. 9cUAB30, 9cUAB124, and 9cUAB130 are three novel retinoid compounds that show cytotoxic effects in other malignancies. We evaluated these novel retinoids in combination with chemotherapy against ovarian cancer stem cells (CSCs) in vitro and in an ex vivo model.
  
  
  METHODS
  A2780 cells were plated in 96-well plates and treated with retinoid, carboplatin, or combination therapy. Cell viability was evaluated using ATPLite assay. The A2780 cell line was also analyzed for CSCs by evaluating ALDH activity using flow cytometry. A2780 cells treated ex vivo with retinoids and chemotherapy were injected into the flank of athymic nude mice in order to evaluate subsequent tumor initiating capacity.
  
  
  RESULTS
  A2780 cells were sensitive to treatment with retinoids and carboplatin. The best treatment resulted from the combination of retinoid 9cUAB130 and carboplatin. Untreated A2780 cells demonstrated ALDH activity in 3.3% of the cell population. Carboplatin treatment enriched ALDH activity to 27.3%, while 9cUAB130±carboplatin maintained the ALDH positive levels similar to untreated controls (2.3% and 6.7%, respectively). Similar results were found in tumorsphere-forming conditions. Flank injections of ex vivo treated A2780 cells resulted in 4/4 mice developing tumors at 40 days in the untreated group, while 0/4 tumors developed in the 9cUAB130 and carboplatin treated group.
  
  
  CONCLUSIONS
  Combination treatment with carboplatin and retinoids reduced cell-viability, reduced CSC marker expression, and inhibited tumorigenicity, making it a more effective treatment when compared with carboplatin alone.
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama, Birmingham, AL, USA. Jenny.Whitworth@obgyn.uab.edu
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Whitworth
authors.forename: Angelina I
authors.initials: AI
authors.lastname: Londoño-Joshi
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Sellers
authors.forename: Patsy J
authors.initials: PJ
authors.lastname: Oliver
authors.forename: Donald D
authors.initials: DD
authors.lastname: Muccio
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Atigadda
authors.forename: J Michael
authors.initials: JM
authors.lastname: Straughn
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012176:Retinoids; D016190:Carboplatin; D000444:Aldehyde Dehydrogenase