title: A novel series of di-fluorinated propanedione derivatives synergistically augment paclitaxel mediated caspase 3 activation in ovarian cancer cells.
abstract: BACKGROUND
  Both chronic and acute inflammatory circuits are known to be associated with malignancy and drug resistance indicating that many antiinflammatory agents can potentially act as chemotherapeutic drugs. A series of new class of propanediones with good antiinflammatory activity were shown to possess moderate cytotoxic activities.
  
  
  OBJECTIVE
  The aim of the study was to evaluate this new series of 1-(2',4'-difluorophenyl)-3-(substituted phenyl)-1,3 propanediones (PR 1-7) for their caspase dependent apoptotic activity by using a reporter gene mediated caspase-3 sensor in chemo sensitive and paclitaxel resistant ovarian cancer cells.
  
  
  METHODS
  A cellular model of paclitaxel resistance was developed in OAW42 cells stably expressing the caspase 3 sensor. The activity of caspase 3 after single and combinatorial drug treatments was determined using western blot and luciferase activity. Cell viability and cell cycle analysis were determined by MTT 3 (4,5- dimethyl thiazol-2 yl-2,5- diphenyl tetrazolium bromide (MTT) and Flow cytometric analysis (FACS) analysis. High Performance Liquid Chromatography (HPLC) analysis was performed to assess cellular uptake of the propanediones.
  
  
  RESULTS
  Both nitro/methoxy (Group I) and halogen substituted propandiones at ortho, meta and para positions (Group II) showed a moderate increase in caspase-3 activity by 1.5- to 3.3-fold as compared with controls. However, no noticeable change in apoptotic cells percentage was observed. Increased intracellular uptake of Paclitaxel was observed during combinatorial treatment with one of the propanediones (PR2). Intriguingly, PR2 alone or in combination with Paclitaxel could induce a 2.5- to 2.9-fold increase in caspase-3 activity in Paclitaxel resistant cells.
  
  
  CONCLUSIONS
  Our study reports a new class of propanediones that can augment the cytotoxic effect of Paclitaxel, and potentially can be used for treating Paclitaxel-resistant cancers.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Nagraj
authors.forename: Subhoshree
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Tanushree
authors.initials: T
authors.lastname: Pal
authors.forename: Asmita S
authors.initials: AS
authors.lastname: Sakpal
authors.forename: Vikram
authors.initials: V
authors.lastname: Gota
authors.forename: C S
authors.initials: CS
authors.lastname: Ramaa
authors.affiliation: Ray Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
authors.forename: Pritha
authors.initials: P
authors.lastname: Ray
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D017239:Paclitaxel