title: Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment.
abstract: BACKGROUND
  Bortezomib is a proteasome inhibitor with minimal clinical activity as a monotherapy in solid tumours, but its combination with other targeted therapies is being actively investigated as a way to increase its anticarcinogenic properties. Here, we evaluate the therapeutic potential of co-treatment with bortezomib and indole-3-carbinol (I3C), a natural compound found in cruciferous vegetables, in human ovarian cancer.
  
  
  METHODS
  We examined the effects of I3C, bortezomib and cisplatin in several human ovarian cancer cell lines. Synergy was determined using proliferation assays and isobologram analysis. Cell cycle and apoptotic effects were assessed by flow cytometry. The mechanism of I3C and bortezomib action was determined by RNA microarray studies, quantitative RT-PCR and western blotting. Antitumour activity of I3C and bortezomib was evaluated using an OVCAR5 xenograft mouse model.
  
  
  RESULTS
  I3C sensitised ovarian cancer cell lines to bortezomib treatment through potent synergistic mechanisms. Combination treatment with bortezomib and I3C led to profound cell cycle arrest and apoptosis as well as disruptions to multiple pathways, including those regulating endoplasmic reticulum stress, cytoskeleton, chemoresistance and carcinogen metabolism. Moreover, I3C and bortezomib co-treatment sensitised ovarian cancer cells to the standard chemotherapeutic agents, cisplatin and carboplatin. Importantly, in vivo studies demonstrated that co-treatment with I3C and bortezomib significantly inhibited tumour growth and reduced tumour weight compared with either drug alone.
  
  
  CONCLUSIONS
  Together, these data provide a novel rationale for the clinical application of I3C and bortezomib in the treatment of ovarian cancer.
authors.affiliation: Women's Cancer Program and Division of Gynecologic Oncology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: B
authors.initials: B
authors.lastname: Taylor-Harding
authors.forename: H
authors.initials: H
authors.lastname: Agadjanian
authors.forename: H
authors.initials: H
authors.lastname: Nassanian
authors.forename: S
authors.initials: S
authors.lastname: Kwon
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: C
authors.initials: C
authors.lastname: Miller
authors.forename: B Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: S
authors.initials: S
authors.lastname: Orsulic
authors.forename: C S
authors.initials: CS
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007211:Indoles; D011719:Pyrazines; D000069286:Bortezomib; C016517:indole-3-carbinol