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Researchers from National University publish new studies and findings in the area of acute promyelocytic leukemia
November 19th, 2007
2007 NOV 19 -- "We have recently reported that PML-RAR-induced mis-folding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation-based therapy for APL," scientists in Singapore, Singapore report. "Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G(2)-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR-induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR," wrote A.P.P. Ng and colleagues, National University. The researchers concluded: "These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells." Ng and colleagues published their study in Molecular Cancer Therapeutics (Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein. Molecular Cancer Therapeutics, 2007;6(8):2240-2248). For more information, contact M. Khan, Singapore National University, School Medical, Oncology Research Institute, 02-07, Center Life Science, 28 Med Dr., Singapore, Singapore. Publisher contact information for the journal Molecular Cancer Therapeutics is: American Association Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA. Keywords: Singapore, Singapore, Acute Promyelocytic Leukemia, Hematology, National University. This article was prepared by Hematology Week editors from staff and other reports. Copyright 2007, Hematology Week via NewsRx.com.
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