Search results for "BCl-2"
showing 10 items of 197 documents
Selective induction of apoptosis in multidrug resistant HL60R cells by the thiazolobenzoimidazole derivative 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3…
1999
We investigated the antitumour effects of 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3,4-a]benzimidazole (TBZ) a new anti-HIV-1 agent, on human promyelocytic HL60 leukaemia, both a parental and a multidrug resistant form (HL60R). HL60R overexpresses P-glycoprotein and, like HL60, lacks p53 protein expression. HL60 and HL60R show similar levels of Bcl-2 protein. In contrast to the conventional chemotherapeutic agents daunorubicin, etoposide and mitoxantrone, TBZ caused equal or even greater cytotoxicity in HL60R than in HL60, and this result was associated with a more marked induction of apoptosis in the drug resistant cells. The antitumour activity of TBZ occurred in the range of concentrations…
SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib.
2007
Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. This paper shows that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) stimulated at 5-10 microM apoptosis in human hepatoma HepG2 and Huh6 cells, but was ineffective in primary human hepatocytes (PHH). In HepG2 cells SAHA induced the extrinsic apoptotic pathway, increasing the expression of both FasL and FasL receptor and causing the activation of caspase-8. Moreover, SAHA enhanced the level of Bim proteins, stimulated alternative splicing of the Bcl-X transcript with the expression of the proapoptotic Bcl-Xs isoform, induced degradation of Bid into the apoptotic factor t-Bid and dephosphorylat…
Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction
2006
Abstract Background Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. Methods RNA interference was per…
Thyroid Cancer Resistance to Chemotherapeutic Drugs via Autocrine Production of Interleukin-4 and Interleukin-10
2003
We investigated the mechanisms responsible for the widespread refractoriness to chemotherapeutic drugs observed in thyroid cancers. We show that malignant epithelial cells from papillary, follicular, and anaplastic thyroid carcinomas express high levels of Bcl-2 and Bcl-xL. Exogenous expression of either Bcl-2 or Bcl-xL in normal thyrocytes was sufficient to prevent chemotherapeutic drug-induced cytotoxicity. All of the histological thyroid cancer variants examined produced interleukin-4 (IL-4) and interleukin-10 (IL-10), which increased Bcl-2 and Bcl-xL levels and protected thyroid cells from chemotherapeutic agents. Exposure to neutralizing antibodies against IL-4 and IL-10 resulted in do…
Expression of type I interferon receptor and its relation with other prognostic factors in human neuroblastoma.
1998
Expression of type I interferon receptor (IFN-R) has been found in several normal tissues and in malignant neoplasms, mainly those with epithelial differentiation. In order to analyze the immunohistochemical expression of type I IFN-R we studied 79 cases of neuroblastoma. Results of expression of type I IFN-R were statistically correlated with histopathology, stage, bcl-2 and PCNA expression, N-myc amplification and apoptosis. We found expression of type I IFN-R in 54/79 cases showing statistical correlation with bcl-2 expression (P=0.017) and favourable histopathology (P=0.015). The overexpression found in ganglion cells suggests that IFN-R could be involved in the pathway of neuroblastoma…
Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation.
2001
Ultraviolet (UV) light is a potent mutagenic and genotoxic agent. Whereas DNA damage induced by UV light is known to be responsible for UV-induced genotoxicity, its role in triggering apoptosis is still unclear. We addressed this issue by comparing nucleotide excision repair (NER) deficient 27-1 and 43-3B Chinese hamster (CHO) cells with the corresponding wild-type and ERCC-1 complemented cells. It is shown that NER deficient cells are dramatically hypersensitive to UV-C induced apoptosis, indicating that DNA damage is the major stimulus for the apoptotic response. Apoptosis triggered by UV-C induced DNA damage is related to caspase- and proteosome-dependent degradation of Bcl-2 protein. Th…
The DNA damage-induced decrease of Bcl-2 is secondary to the activation of apoptotic effector caspases.
2003
Apoptosis induced by DNA-damaging agents or radiation mainly proceeds through death receptor-independent caspase activation. The release of mitochondrial apoptogenic proteins, such as cytochrome c, into the cytoplasm leading to Apaf1-dependent activation of caspase-9 is a key event in this pathway. The permeability of the mitochondrial outer membrane is regulated by the various pro- and antiapoptotic Bcl-2 family proteins, and it is thought that DNA damage triggers apoptosis through the downregulation of antiapoptotic Bcl-2. Using murine embryonic fibroblasts (MEF) deficient and proficient in Apaf1, we show that DNA-damaging agents and radiation lead to a decline in Bcl-2 protein only in wt…
Tumoricidal activity of endothelium-derived NO and the survival of metastatic cells with high GSH and Bcl-2 levels.
2008
Metastatic spread, not primary tumor burden, is the leading cause of cancer death. Glutathione (L-gamma-glutamyl-L-cysteinyl-glycine; GSH) is the most prevalent non-protein thiol in mammalian cells, and in cancer cells is particularly relevant in regulating mutagenic mechanisms, DNA synthesis, growth, and multidrug and radiation resistance. In malignant tumors, as compared with normal tissues, that resistance associates in most cases with higher GSH levels. Interaction of metastatic cells with the vascular endothelium activates local release of proinflammatory cytokines, which act as signals promoting cancer cell adhesion, extravasation, and proliferation. A high% of metastatic cells with h…
Apoptotic induction in transformed follicular lymphoma cells by Bcl-2 downregulation.
1998
The roles of Bcl-2 protein and the protein ratio of Bcl-2/Bax in regulating cell growth in various lymphoma cell lines were examined. A dose-dependent decrease in Bcl-2 protein expression was observed in the different lymphomas incubated with lipid-incorporated bcl-2 antisense oligonucleotides (L-bcl-2). Growth inhibition was observed in a transformed follicular lymphoma (FL) cell line, which has the t(14;18) translocation and Bcl-2 protein overexpression. One of the mechanisms by which L-bcl-2 growth inhibition is mediated in these transformed FL cells might be through apoptotic induction, because the treated cells had an increased apoptotic index and showed the typical DNA fragmentation. …
The new iodoacetamidobenzofuran derivative TR120 decreases STAT5 expression and induces antitumor effects in imatinib-sensitive and imatinib-resistan…
2013
The identification of novel compounds modulating the expression/activity of molecular targets downstream to BCR-ABL could be a new approach in the treatment of chronic myeloid leukemias (CMLs) resistant to imatinib or other BCR-ABL-targeted molecules. Recently, we synthesized a new class of substituted 2-(3,4,5-trimethoxybenzoyl)-2-N,N-dimethylamino-benzo[b]furans, and among these 3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone (TR120) showed marked cytotoxic activity in BCR-ABL-expressing cells. Interestingly, TR120 was more potent than imatinib in cell growth inhibition and apoptosis induction in both BCR-ABL-expressing K562 and KCL22 cells. Moreover, it showed a…