Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amino terminus truncated p73 isoform, DeltaNp73alpha, shows dominant negative behavior toward TAp73 and wild-type p53, and has oncogenic potential. By contrast, we recently showed that in HCT116 clones forced expression of DeltaNp73alpha did not increase in vitro cellular resistance to anticancer agents. The purpose of this study was to characterize in vivo models and to investigate the functional interaction between the DeltaNp73alpha isoform and the p53 pathway. Human colon carcinoma HCT116 clones expressing inducible DeltaNp73alpha (HCT116/DN3, HCT116/DN14) and HCT116/8a (transfected with the mock empty vector), transplanted in immunodeficient nude mice, were used to study the antitumor activity of cis-diammine-dichloro-platinum (cDDP) (4 mg/kg, i.v., q7d x 3) and Doxorubicin (DX) (7.5 mg/kg, i.v., q7d x 3), with or without tetracycline-induced DeltaNp73alpha overexpression. DeltaNp73alpha expression was confirmed by RT-PCR, immunoblotting and immunohistochemical analysis. DeltaNp73alpha subcellular localization after DX treatment was checked by an immunofluorescence assay. Western blot was used to analyze p53, p21, Bax, Bcl-2 and p53AIP1 expression. DeltaNp73alpha overexpression did not modify the antitumor activity of either DX or cDDP in xenograft models. DX reduced DeltaNp73alpha protein expression, without affecting its nuclear localization. p53, p21, Bax and p53AIP1 protein expression increased and Bcl-2 decreased in HCT116 clone derived tumors 24 hr after DX exposure, independently of the presence of DeltaNp73alpha. Overexpression of DeltaNp73alpha does not affect tumor growth in vivo, does not increase the resistance of established tumors to anticancer agents and does not antagonize p53 apoptotic functions.
 ...
PMID:In vivo evaluation of the role of DNp73alpha protein in regulating the p53-dependent apoptotic pathway after treatment with cytotoxic drugs. 1709 33

Currently, Arsenic Trioxide (ATO) is considered the treatment of choice for patients with relapsed acute promyelocytic leukemia (APL). Recently, a durable remission with minimal toxicity by single agent ATO or ATO + ATRA in newly diagnosed APL was reported by different groups. These regimens have minimal toxicity and can be administered on an outpatient basis after remission induction, thus they could become a real, less toxic and more economic option to ATRA + anthracyclines in particular in low risk APL, or in patients that cannot undergo chemotherapy because of age or comorbid conditions and in patients that refuse chemotherapy. Significantly, these therapies are a successful attempt to cure a tumoral disease without chemotherapy. The results of clinical trials of ATO administration as single agent in multiple myeloma (MM) and myelodisplastic syndromes (MDS) were encouraging and showed clinical effects but they were not close to APL success. On the contrary, results of clinical trials to treat non-APL acute myeloid leukemia (AML) were disappointing. We suggest that a combination therapy with drugs targeting specific pro-survival molecules or capable to enhance pro-apoptotic pathways may lead to an improvement of ATO efficacy against hematological malignancies, in particular AML. Our pre-clinical studies showed that ATO is capable to induce cell death in acute leukemia cells but the apoptotic function is limited since it can induce also a mechanism of cell defense by activating pro-survival molecules such as MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK inhibitors, we demonstrated that the block of MEK-ERK phosphorylation, the induction of Bad de-phosphorylation, and activation of p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms of ATO and kill the leukemic cells by apoptotic synergism. Our results provide an experimental basis for combined or sequential treatment with MEK inhibitors and ATO in AML. The renaissance of ATO as a drug in moderne medicine may be considered, together with ATRA success, a victory of empirical analysis, that had (and has) great impact on Chinese culture.
 ...
PMID:Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug. 1716 55

The expression of growth hormone-releasing hormone (GHRH) and its receptors has been demonstrated in peripheral tissues as well as CNS. Recently, the functional splice variant SV1 of GHRH receptor was identified in various human cancers and cancer cell lines. Although antineoplastic activity of GHRH antagonists has been clearly demonstrated, the mechanism of action is incompletely understood. The objective of this study was the investigation of direct anti-proliferative effect of GHRH antagonist MZ-5-156 on HEC-1A human endometrial cancer cell line and the elucidation of underlying mechanisms. RT-PCR revealed the expression of mRNA for GHRH and SV1 of GHRH receptor in HEC-1A cells. MZ-5-156, at concentrations between 10(-7) and 10(-5) M, had a dose-dependent antiproliferative effect on HEC-1A cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, (MTS) assay. Hoechst 33342 staining and flow cytometric analysis indicated that MZ-5-156, at 10(-6) M, induced apoptosis in HEC-1A cells after 48 h of treatment. Western blot analysis of apoptosis-related proteins demonstrated that treatment with MZ-5-156 (10(-6) M) for 48 h significantly increased the protein levels of Fas, phospho-p53 (Ser46), p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1), and caspase-8, -9, and -3, and decreased the protein level of Bcl-2. These results demonstrate that MZ-5-156 can directly inhibit the proliferation of human endometrial cancer cells, which express mRNA for GHRH and SV1 of GHRH receptor, presumably through the induction of p53-dependent apoptosis coupled with the up-regulation of Fas, phospho-p53 (Ser46), p53AIP1, and caspase-8, -9, and -3, and the down-regulation of Bcl-2.
 ...
PMID:Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone. 1829 36

S-diclofenac (2-[(2,6-dichlorophenyl) amino] benzene acetic acid 4-(3H-1,2,dithiol-3-thione-5-yl) phenyl ester) is a novel molecule comprising a hydrogen sulfide (H2S)-releasing dithiol-thione moiety attached by an ester linkage to diclofenac. Effect of S-diclofenac (H2S donor) on cell proliferation was investigated on the primary and immortalized rat aortic vascular smooth muscle cells (SMC). Smooth muscle cell proliferation has been considered as a key event in vascular injury in diseases such as atherosclerosis and restenosis after invasive intervention. Clonogenic cell survival assay showed a dose dependent (10-100 microM) decrease in cell survival. Flow cytometric analysis showed that the asynchronized cells are more sensitive than the cells that are synchronized and revealed that the cells in G1 phase are not affected by the treatment of the S-diclofenac. Asynchronized smooth muscle cells treated with the S-diclofenac showed an increase in apoptotic cell death. S-diclofenac treatment also resulted in stabilization of p53 coupled with the induction of downstream proteins such as p21, p53AIP1 and Bax. S-diclofenac did not up-regulate cell levels of the antiapoptotic protein Bcl-2. However, when the cells are synchronized a stimulatory effect of cell growth with the decrease in apoptosis, p53 and p21 was evident. S-diclofenac inhibits smooth muscle cell growth and may play a role in the lesion formation at sites of the vascular injury. The present results suggest that S-diclofenac may be useful for the prevention of smooth muscle cell proliferation in diseases such as vascular obstructive and restenosis.
 ...
PMID:Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative inhibit rat vascular smooth muscle cell proliferation. 1868 Jul 41