Posted by rob on September 30, 2011 under Uncategorized | 
The in-vitro antiproliferative effect of PRI-2191 and imatinib applied in combined treatment with cisplatin, idarubicin, or docetaxel on human leukemia cells.
Anticancer Drugs. 2011 Sep 22;
Authors: Switalska M, Nasulewicz-Goldeman A, Opolska A, Maciejewska M, Kutner A, Wietrzyk J
Abstract
Imatinib mesylate (Gleevec, STI571) is a specific inhibitor of the Bcr/Abl fusion tyrosine kinase that exhibits potent antileukemic effects in chronic myelogenous leukemia. Bcr/Abl-positive K562 and Bcr/Abl-negative HL-60 human leukemia cells were used to investigate the effect of PRI-2191, a calcitriol analog, on the biological effects of imatinib combined with other anticancer drugs.The results show that PRI-2191 enhances the antiproliferative effect of imatinib on HL-60 cells. When these two agents together are applied with either docetaxel or cisplatin, but not with idarubicin, the antiproliferative effect could still be enhanced. Moreover, when the interaction between the chemotherapy agents was antagonistic or additive, PRI-2191 could even shift it to synergism. This effect correlated with an accumulation of HL-60 cells in the G0/G1 phase of the cell cycle and a decrease in the percentage of cells in the G2/M and S stage in the ternary combinations used. PRI-2191 did not influence apoptosis induced by imatinib alone or in ternary combinations with all the chemotherapy agents used. These results may suggest that the stronger antiproliferative effect of the combined treatment with PRI-2191 on HL-60 cells is related to cell cycle arrest rather than to the induction of apoptosis.
PMID: 21934605 [PubMed - as supplied by publisher]
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HSPB8 is methylated in hematopoietic malignancies and overexpression of HSPB8 exhibits antileukemia effect.
Exp Hematol. 2011 Sep 10;
Authors: Cui XY, Wang N, Yang BX, Gao WF, Lin YM, Yao XR, Ma XT
Abstract
HSPB8 has been shown to be involved in regulation of cell proliferation and apoptosis, and it has also been found to have divergent properties in solid tumors. The purpose of this study was to investigate the expression and function of HSPB8 in hematopoietic malignancies. Expression and induced expression of HSPB8 was evaluated in hematopoietic tumor cell lines and bone marrow samples from patients with leukemia. Methylation status was investigated by methylation-specific polymerase chain reaction. The role of HSPB8 in hematopoietic malignancies was addressed by reintroducing HSPB8 expression into the K562 (leukemia) and Namalwa (lymphoma) cell lines. Expression of HSPB8 was absent in hematopoietic tumor cell lines and primary patient and normal volunteer samples. Promoter DNA methylation of HSPB8 was observed in these cells. HSPB8 expression could be restored after demethylation treatment with 5-aza-2′-deoxycytidine. Overexpression of HSPB8 reduced colony formation of both K562 and Namalwa cell lines, inhibited the cell growth of Namalwa in vitro, and suppressed tumor formation of K562 cells in vivo. The present study demonstrates that HSPB8 is silenced by DNA methylation in hematopoietic malignant and normal cells and its expression can be induced by treatment with 5-aza-2′-deoxycytidine. Overexpression of HSPB8 may have an antitumor activity in chronic myelogenous leukemia and lymphoma.
PMID: 21914495 [PubMed - as supplied by publisher]
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Crk-associated substrate lymphocyte type regulates myeloid cell motility and suppresses the progression of leukemia induced by p210Bcr/Abl.
Cancer Sci. 2011 Aug 16;
Authors: Seo S, Nakamoto T, Takeshita M, Lu J, Sato T, Suzuki T, Kamikubo Y, Ichikawa M, Noda M, Ogawa S, Honda H, Oda H, Kurokawa M
Abstract
The p210Bcr/Abl and p190Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. Crk-associated substrate lymphocyte type (Cas-L)/human enhancer of filamentation-1 (HEF1)/neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is an adapter protein at focal adhesions known to be associated with solid tumor metastasis. Crk-associated substrate lymphocyte type has also been reported to be tyrosine phosphorylated by p190Bcr/Abl. We demonstrated that Cas-L was expressed in murine granulocytes, as well as in lymphocytes, and that Cas-L-deficient (Cas-L(-/-) ) granulocytes had increased migratory activity and decreased adhesiveness. To examine whether Cas-L was involved in leukemogenesis by p210Bcr/Abl, we generated Cas-L(-/-) p210Bcr/Abl transgenic mice. The mice displayed early development of myeloproliferative neoplasm seen in the chronic phase of CML, which resulted in the early death of the mice. Pathologically, increased infiltration of myeloid cells into several tissues was detected in the absence of Cas-L. In a hematopoietic reconstitution assay, Cas-L(-/-) p210Bcr/Abl transgenic cells showed a low population in the spleen, although only their myeloid cell population was normal. Thus, Cas-L seems to regulate the progression of CML in a negative way, presumably by attenuating extramedullary hyperplasia. (Cancer Sci, doi: 10.1111/j.1349-7006.2011.02066.x, 2011).
PMID: 21848808 [PubMed - as supplied by publisher]
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Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids.
ACS Med Chem Lett. 2011 Feb;2(2):113-118
Authors: Bobkova EV, Liu WH, Colayco S, Rascon J, Vasile S, Gasior C, Critton DA, Chan X, Dahl R, Su Y, Sergienko E, Chung TD, Mustelin T, Page R, Tautz L
Abstract
Protein tyrosine phosphatases (PTPs) have only recently become the focus of attention in the search for novel drug targets despite the fact that they play vital roles in numerous cellular processes and are implicated in many human diseases. The hematopoietic protein tyrosine phosphatase (HePTP) is often found dysregulated in preleukemic myelodysplastic syndrome (MDS), as well as in acute myelogenous leukemia (AML). Physiological substrates of HePTP include the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Specific modulators of HePTP catalytic activity will be useful for elucidating mechanisms of MAPK regulation in hematopietic cells, and may also provide treatments for hematopoietic malignancies such as AML. Here we report the discovery of phenoxyacetic acids as inhibitors of HePTP. Structure-activity relationship (SAR) analysis and in silico docking studies reveal the molecular basis of HePTP inhibition by these compounds. We also show that these compounds are able to penetrate cell membranes and inhibit HePTP in human T lymphocytes.
PMID: 21503265 [PubMed - as supplied by publisher]
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A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer.
Cancer Chemother Pharmacol. 2011 Oct;68(4):1033-44
Authors: Ahmed AA, Goldsmith J, Fokt I, Le XF, Krzysko KA, Lesyng B, Bast RC, Priebe W
Abstract
PURPOSE: To investigate the mechanistic basis of the anti-tumor effect of the compound ITB-301.
METHODS: Chemical modifications of genistein have been introduced to improve its solubility and efficacy. The anti-tumor effects were tested in ovarian cancer cells using proliferation assays, cell cycle analysis, immunofluorescence, and microscopy.
RESULTS: In this work, we show that a unique glycoside of genistein, ITB-301, inhibits the proliferation of SKOv3 ovarian cancer cells. We found that the 50% growth inhibitory concentration of ITB-301 in SKOv3 cells was 0.5 ?M. Similar results were obtained in breast cancer, ovarian cancer, and acute myelogenous leukemia cell lines. ITB-301 induced significant time- and dose-dependent microtubule depolymerization. This depolymerization resulted in mitotic arrest and inhibited proliferation in all ovarian cancer cell lines examined including SKOv3, ES2, HeyA8, and HeyA8-MDR cells. The cytotoxic effect of ITB-301 was dependent on its induction of mitotic arrest as siRNA-mediated depletion of BUBR1 significantly reduced the cytotoxic effects of ITB-301, even at a concentration of 10 ?M. Importantly, efflux-mediated drug resistance did not alter the cytotoxic effect of ITB-301 in two independent cancer cell models of drug resistance.
CONCLUSION: These results identify ITB-301 as a novel anti-tubulin agent that could be used in cancers that are multidrug resistant. We propose a structural model for the binding of ITB-301 to ?- and ?-tubulin dimers on the basis of molecular docking simulations. This model provides a rationale for future work aimed at designing of more potent analogs.
PMID: 21340606 [PubMed - in process]
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