Search

Four dinuclear osmium complexes have been constructed for antitumor phototherapy. The most potent Os4 has extremely high photothermal conversion capability under irradiation of an 808 nm low-power laser, targets mitochondria in human melanoma cells without nucleus affinity, and acts as an antitumor photothermal therapy agent in vitro and in vivo .

Lipid rafts mediate several survival signals in the development of chronic myeloid leukemia (CML). Methyl-β-cyclodextrin (MβCD) is an inhibitor specifically designed to disrupt lipid rafts in cells by depleting the cholesterol component. We hypothesize that treatment of CML cells with MβCD and imatinib could reduce imatinib resistance. Apoptotic and autophagic cell death was assayed using annexin V-propidium iodide double staining, immunoblotting, and immunocytochemistry. We next investigated whether MβCD could enhance the cytotoxicity of imatinib in imatinib-sensitive and imatinib-resistant K562 cells. Extracellular signal-regulated kinase/sphingosine kinase 1 signaling downstream of lipid raft-activated signaling pathways was significantly inhibited by treatment of cells with a combination of MβCD and imatinib compared with treatment with either agent alone. MβCD induces programmed cell death in CML cells, and its antileukemia action is synergistic with that of imatinib.

Interactions between the proteasome inhibitor, bortezomib, and the sphingosine kinase (SPK1) inhibitor, SKI, were examined in BCR/ABL human leukemia cells. Coexposure of K562 or chronic myeloid leukemia (CML) cells from patients to subtoxic concentrations of SKI (10 μM) and bortezomib (100 nM) resulted in a synergistic increase in caspase-3 cleavage and apoptosis. These events were associated with the downregulation of BCR-ABL and Mcl-1, and a marked reduction in SPK1 expression. In imatinib mesylate-resistant K562 cells that displayed decreased BCR-ABL expression, bortezomib/SKI treatment markedly increased apoptosis and inhibited colony-formation in association with the downregulation of Mcl-1. Finally, the bortezomib/SKI regimen also potently induced the downregulation of BCR/ABL and Mcl-1 in human leukemia cells. Collectively, these findings suggest that combining SKI and bortezomib may represent a novel strategy in leukemia, including apoptosis-resistant BCR-ABL(+) hematologic malignancies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Spreds, a recently established class of negative regulators of the Ras-ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras-ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML., (Copyright 2010 Elsevier Inc. All rights reserved.)

Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC 50 values ranging from 15 to 40 nM), especially HeLa cells (with IC 50 values of 15 nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug. [ABSTRACT FROM AUTHOR]