title: HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) usually responds well to initial therapy but is prone to relapses with chemoresistant disease, indicating the need for novel therapeutic approaches. Inhibition of the p53 E3 ligase human homolog of the murine double minute protein-2 (HDM-2) with MI-63 has been validated as one such strategy in wild-type (wt) p53 models, and our genomic and proteomic analyses demonstrated that MI-63 suppressed the expression of the ribonucleotide reductase (RNR) subunit M2 (RRM2). This effect occurred in association with induction of p21 and cell-cycle arrest at G(1)/S and prompted us to examine combinations with the RNR inhibitor 2',2'-difluoro-2'-deoxycytidine (gemcitabine). The regimen of MI-63-gemcitabine induced enhanced, synergistic antiproliferative, and proapoptotic effects in wtp53 MCL cell lines. Addition of exogenous dNTPs reversed this effect, whereas shRNA-mediated inhibition of RRM2 was sufficient to induce synergy with gemcitabine. Combination therapy of MCL murine xenografts with gemcitabine and MI-219, the in vivo analog of MI-63, resulted in enhanced antitumor activity. Finally, synergy was seen with MI-63-gemcitabine in primary patient samples that were found to express high levels of RRM2 compared with MCL cell lines. These findings provide a framework for translation of the rational combination of an HDM-2 and RNR inhibitor to the clinic for patients with relapsed wtp53 MCL.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. rjones@mdanderson.org
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.forename: Sattva
authors.initials: S
authors.lastname: Neelapu
authors.forename: Luis E
authors.initials: LE
authors.lastname: Fayad
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Romaguera
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sharma
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000819:agonists / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000819:agonists / Q000494:pharmacology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000096:biosynthesis*; D016196:S Phase / Q000187:drug effects; D013141:Spiro Compounds / Q000819:agonists / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D007211:Indoles; C543589:MI-63 compound; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000093542:Gemcitabine