Journal article
Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells
Molecular cancer therapeutics, Vol.8(6), pp.1473-1483
06/2009
Handle:
https://hdl.handle.net/2376/118315
PMCID: PMC3415237
PMID: 19509254
Abstract
The Pim protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim protein kinase inhibitors. With IC
50
values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and proteins
in vitro
and, when added to DU145 prostate cancer cells overex-pressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH
3
protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G
1
-S cell cycle arrest and block the antiapoptotic effect of the Pim protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27
Kip1
, a cyclin-dependent kinase 2 inhibitory protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim protein kinases in cell cycle control in multiple types of cancer cells.
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Details
- Title
- Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells
- Creators
- Zanna Beharry - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Charleston, South CarolinaMarina Zemskova - Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South CarolinaSandeep Mahajan - Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South CarolinaFengxue Zhang - Medical University of South CarolinaJian Ma - Department of Medicine, Medical University of South Carolina, Charleston, South CarolinaZuping Xia - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Charleston, South CarolinaMichael Lilly - Center for Health Disparities and Molecular Medicine, Departments of Medicine and Microbiology, Loma Linda University School of Medicine, Loma Linda, CaliforniaCharles D Smith - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Charleston, South CarolinaAndrew S Kraft - Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Publication Details
- Molecular cancer therapeutics, Vol.8(6), pp.1473-1483
- Academic Unit
- Department of Pharmaceutical Sciences; College of Pharmacy and Pharmaceutical Sciences
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 11
- Grant note
- P30 CA138313 || CA / National Cancer Institute : NCI
- Identifiers
- 99900547863101842
- Language
- English
- Resource Type
- Journal article