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ABSTRACT: 7b, a novel amonafide analog, has shown high antitumor activity against Raji B-cell lymphoma. We report here that 7b also shows high cytotoxicity against various T lymphoma cells, with the highest IC(50) (concentration for 50% cytotoxicity) value in Jurkat cells. In a previous study, p53-mutant Raji cells were sensitive to 7b treatment. In the present study, the Jurkat T lymphoma cells were characterized as p53-null. Additional assays showed that 7b could induce G1/S phase arrest and mitochondrial apoptosis in Jurkat cells, suggesting 7b as a potential drug candidate for treatment of T-cell lymphoma. This action was not affected by p53 status. Further analysis of molecular mechanisms revealed that up-regulation of p21 and the Bak/Bcl-2 ratio and down-regulation of UHRF1 and c-Myc were attributed to p73 activation. In turn, up-regulation of p73 was initiated by DNA damage-induced reactive oxygen species (ROS) formation. Interestingly, at non-toxic drug concentrations, 7b could also inhibit phorbol 12-myristate 13-acetate/phytohemagglutinin (PMA/PHA)-induced inflammatory responses of Jurkat T cells owing to the suppression of nuclear factor-κB (NF-κB) DNA-binding. Indeed, electrophoretic mobility shift assay and NF-κB binding assay showed that NF-κB DNA-binding was inhibited by 7b, and correspondingly, proinflammatory cytokine production was also decreased. In conclusion, 7b exhibits both antiproliferative and anti-inflammatory activities in T lymphoma cells.
Leukemia & lymphoma 07/2012; · 2.40 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in tumor metastasis. In this study, we describe the down-regulation and function of miR-139 in colorectal cancer (CRC) metastasis. MiR-139 was found underexpressed in 34 CRC tissues compared to their corresponding nontumor tissues. Decreased miR-139 in CRC tissue was associated with disease progression and metastasis. Re-expression of miR-139 did not inhibit CRC cell growth but suppresses CRC cell metastasis and invasion in vitro and in vivo. MiR-139 might suppress CRC cells invasion and metastasis by targeting type I insulin-like growth factor receptor (IGF-IR). We also found miR-139 directed migration inactivation of human CRC cells involves down-regulation of matrix metalloproteinase 2 (MMP-2). The IGF-IR/MEK/ERK signaling was inhibited by miR-139 overexpression and then resulted in MMP-2 promoter suppression. Taken together, our results provide evidence that miR-139 might function as a metastasis suppressor in CRC. Targeting miR-139 may provide a strategy for blocking CRC metastasis.
Biochemical pharmacology 05/2012; 84(3):320-30. · 4.25 Impact Factor
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ABSTRACT: The emergence of multidrug resistance (MDR) in cancer cells has made many of the currently available chemotherapeutic agents ineffective. However, the mechanism involved in mediating this effect is not yet fully understood. Here, we found the overexpression of type I insulin-like growth factor receptor (IGF-IR) in established colorectal MDR cells. Specific siRNA of IGF-IR decreases cell proliferation, exert synergistic effect with anticancer drugs. The downstream signaling of IGF-IR, PI3K/AKT pathway, was altered upon IGF-IR silencing. The expression of multidrug-resistance-associated protein 2 (MRP-2) was suppressed due to the nuclear translocation of nuclear factor-like 2 (Nrf2). Then the intracellular drug concentration was increased and the drug-resistant phenotype was reversed. Our findings improve current understanding of the biology of IGF-IR and MDR and have significant therapeutic implications on colorectal MDR cancer.
Journal of Cellular Biochemistry 01/2012; 113(6):2086-97. · 2.87 Impact Factor
