Faculty Collaboration Database

CDDO-Imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms. Mol Cancer 2006 Jun 07;5:22

Date

06/09/2006

Pubmed ID

16759389

Pubmed Central ID

PMC1553469

DOI

10.1186/1476-4598-5-22

Scopus ID

2-s2.0-33748131759 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

BACKGROUND: Gene-targeted iMycEmu mice that carry a His6-tagged mouse Myc(c-myc)cDNA, MycHis, just 5' of the immunoglobulin heavy-chain enhancer, Emu, are prone to B cell and plasma cell neoplasms, such as lymphoblastic B-cell lymphoma (LBL) and plasmacytoma (PCT). Cell lines derived from Myc-induced neoplasms of this sort may provide a good model system for the design and testing of new approaches to prevent and treat MYC-driven B cell and plasma cell neoplasms in human beings. To test this hypothesis, we used the LBL-derived cell line, iMycEmu-1, and the newly established PCT-derived cell line, iMycEmu-2, to evaluate the growth inhibitory and death inducing potency of the cancer drug candidate, CDDO-imidazolide (CDDO-Im).

METHODS: Morphological features and surface marker expression of iMycEmu-2 cells were evaluated using cytological methods and FACS, respectively. mRNA expression levels of the inserted MycHis and normal Myc genes were determined by allele-specific RT-PCR and qPCR. Myc protein was detected by immunoblotting. Cell cycle progression and apoptosis were analyzed by FACS. The expression of 384 "pathway" genes was assessed with the help of Superarray cDNA macroarrays and verified, in part, by RT-PCR.

RESULTS: Sub-micromolar concentrations of CDDO-Im caused growth arrest and apoptosis in iMycEmu-1 and iMycEmu-2 cells. CDDO-Im-dependent growth inhibition and apoptosis were associated in both cell lines with the up-regulation of 30 genes involved in apoptosis, cell cycling, NFkappaB signaling, and stress and toxicity responses. Strongly induced (> or = 10 fold) were genes encoding caspase 14, heme oxygenase 1 (Hmox1), flavin-containing monooxygenase 4 (Fmo4), and three members of the cytochrome P450 subfamily 2 of mixed-function oxygenases (Cyp2a4, Cyp2b9, Cyp2c29). CDDO-Im-dependent gene induction coincided with a decrease in Myc protein.

CONCLUSION: Growth arrest and killing of neoplastic mouse B cells and plasma cells by CDDO-Im, a closely related derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid, appears to be caused, in part, by drug-induced stress responses and reduction of Myc.

Author List

Han SS, Peng L, Chung ST, DuBois W, Maeng SH, Shaffer AL, Sporn MB, Janz S

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
B-Lymphocytes
Cell Line
Cell Proliferation
Cell Survival
DNA, Complementary
Gene Expression Regulation, Neoplastic
Imidazolidines
Mice
Mice, Transgenic
NF-kappa B
Oleanolic Acid
Oligonucleotide Array Sequence Analysis
Plasmacytoma
Proto-Oncogene Proteins c-myc
Transcriptional Activation
Up-Regulation