title: Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib.
abstract: OBJECTIVE
  p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM).
  
  
  METHODS
  We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3.
  
  
  RESULTS
  The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells.
  
  
  CONCLUSIONS
  This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy.
authors.affiliation: Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Ooi
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hayden
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Elpida
authors.initials: E
authors.lastname: Charalambous
authors.forename: Emily
authors.initials: E
authors.lastname: Daskalaki
authors.forename: Noopur S
authors.initials: NS
authors.lastname: Raje
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Leutz
authors.initials: L
authors.lastname: Buon
authors.forename: Martin
authors.initials: M
authors.lastname: Clynes
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gorman
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D020125:Mutation, Missense; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007093:Imidazoles; D010879:Piperazines; D061988:Proteasome Inhibitors; D011719:Pyrazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D000069286:Bortezomib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex