Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vinorelbine (NVB) is a novel vinca alkaloid FDA approved for use in some advanced carcinomas. However, its role in non-Hodgkin's lymphoma (NHL) is still not well defined. NVB is an antimicrotubule agent, but as yet, it is not known whether it induces apoptosis. By flow cytometry using nuclear staining (propidium iodide) and annexin V, we demonstrated that NVB and vincristine (VCR) induced both mitotic arrest and apoptosis in leukemia and lymphoma cells, in a drug exposure time dependent manner. Cell cycle kinetics in 3 different cell lines varied during vinca alkaloid treatment. The annexin V method showed that apoptosis, as opposed to necrosis, was the dominant mode of cell kill of chemosensitive leukemia and lymphoma cells. Phosphatidylserine expression on the cell surface was detectable as a hallmark of apoptosis at earlier drug exposure when compared to conventional flow cytometry with PI staining. By Western blot analysis, we demonstrated that CPP32 or caspase-3, a critical apoptosis inducer, and its active subunits p20 and p11 were upregulated in chemo- and apoptosis-sensitive lymphoma and leukemia cells treated with NVB. Our data contributes to the emerging hypothesis suggesting that widely divergent exogenous stimuli and chemotherapeutic agents can effect apoptosis in cancer cells via different pathways involving the caspases. We believe that vinorelbine may be a potentially important drug in the treatment of NHL in the future.
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PMID:Vinorelbine induces apoptosis and caspase-3 (CPP32) expression in leukemia and lymphoma cells: a comparison with vincristine. 972 Jul 29

Lung cancers are among the most frequent and the most lethal tumours. They are mainly treated by surgery or by chemotherapy, but in the most advanced stages a local cryotherapy can be proposed as a palliative option for bronchial clearance. This therapy, based on the cytotoxic effects of low temperatures, acts by mechanisms which are not yet totally understood. The aim of this work was to investigate in vivo the biological effects of cryotherapy in a model of human non-small-cell lung cancer. We used a xenograft system: cells from the A549 cell line (adenocarcinoma) were injected subcutaneously into SCID mice. Cryotherapy was performed (three cycles, nitrous oxide cryoprobe). Chemotherapy (intravenous injection of Vinorelbine (Navelbine), 4.8 mg/kg) was used as a control treatment. Tumour nodes were excised at variable time points and studied morphologically. The induction of apoptosis was analysed by immunohistochemical staining of cleaved caspase-3 and by TUNEL. Results showed that cryotherapy was an efficient technique to induce cell death either by necrosis or by apoptosis. Necrosis was found near the cryoprobe impact site and was maximal 2 h after treatment (65%); a second peak was observed after 4 days (77%). Around this central necrotic area, apoptotic cells were found. Apoptosis was maximal after 8 h (47%). Chemotherapy induced apoptosis in a fewer number of cells and this effect was not time-dependent. Taken together, these results demonstrate the differential effects of cryotherapy and chemotherapy in vivo, suggesting different modes of action and the potential benefit to combine them.
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PMID:Effects of cryotherapy or chemotherapy on apoptosis in a non-small-cell lung cancer xenografted into SCID mice. 1571 Mar 67

Elderly lung cancer patients and those with poor performance status/co-morbid conditions are deprived of chemotherapy because of high toxicity of multidrug regimens. Human squamous cell lung carcinoma H520 cells treated with Curcumin were sensitized to the cytotoxicity caused by chemotherapeutic agent, Vinorelbine. Both caused apoptosis by increasing the protein expression of Bax and Bcl-xs while decreasing Bcl-2 and Bcl-X(L), releasing apoptogenic cytochrome c, and augmenting the activity of caspase-9 and caspase-3. Expression of Cox-2, NF-kappaB, and AP-1 was also affected. 23.7% apoptosis was induced in the H520 cells by treatment with Curcumin while Vinorelbine caused 38% apoptosis. Pre-treatment with Curcumin enhanced the Vinorelbine induced apoptosis to 61.3%. The findings suggest that Curcumin has the potential to act as an adjuvant chemotherapeutic agent and enhance chemotherapeutic efficacy of Vinorelbine in H520 cells in vitro. Thus, Curcumin offers the prospect of being beneficial in the above-mentioned patient groups.
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PMID:Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. 1588 9

Cryotherapy, an efficient technique to destroy tumour cells, is sometimes applied locally as a palliative treatment in lung cancers. It can be performed in combination with chemotherapy. Our aims were to determine in vivo: (1) the effects of cryochemotherapy in a human lung adenocarcinoma, (2) if it presents a benefit compared to the separate treatments and (3) if cryotherapy allows a tumour retention of the drug. Cells from the A549 cell line were xenografted into SCID mice. Tumours were treated by cryotherapy, chemotherapy (injection of Vinorelbine: Navelbine) or both and were studied morphologically at variable time points. Apoptosis was analysed by immunohistochemical staining of cleaved caspase-3 and by TUNEL. Intratumour Navelbine concentration was assessed by high performance liquid chromatography. Necrosis was important 2 h after cryochemotherapy (45% of the tumour surface) and at the later time points. Expression of cleaved caspase-3 was not significantly different from that of untreated tumours, except at the time point of 2 h where it was maximal (58%). Navelbine concentration was more important in tumours treated by chemotherapy than in tumours treated by cryochemotherapy, demonstrating that in our model, the benefit of the association observed 2h after treatment was not due to a concentration-dependent effect.
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PMID:In vivo cryochemotherapy of a human lung cancer model. 1596 88

In the treatment of lung cancers, a local cryotherapy can be proposed as a palliative option for bronchial clearance. But this therapy can also be used as an adjuvant treatment, for instance in association with chemotherapy. We have already demonstrated differential biological effects of these therapies and the benefit to combine them. The aim of this study was to determine if this benefit observed at a molecular level was correlated with tumour growth. As vascular changes occur after cryotherapy, intratumoral angiogenesis was also studied. Cells from the A549 cell line were inoculated into SCID mice. Tumours were treated by cryotherapy (nitrous oxide cryoprobe), chemotherapy (injection of Vinorelbine) or both. Tumour growth was studied in each group and the T/C ratios were compared. Tumours treated by cryochemotherapy presented a significantly reduced volume and the lower T/C ratio, confirming the benefit of a combined treatment. Angiogenesis was assessed at variable time points after cryotherapy by immunohistochemical staining of VEGF and western blot analysis. A late cryo-induced angiogenesis was observed 8-15 days after treatment (expression of VEGF increased from 13% in untreated tumours to 77 and 70%, respectively). To determine if this hypervascularization could enhance the efficiency of chemotherapy, the drug was injected 15 days after cryotherapy and the induction of cell death was investigated (morphological study, immunohistochemical staining of cleaved caspase-3, TUNEL). Necrosis was increased but not apoptosis, suggesting that though a crucial parameter, intratumoral microvessel density is not the only factor to consider to reach an optimal efficiency of a combined treatment.
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PMID:Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model. 1688 70

Vinorelbine is a chemotherapeutic vinca alkaloid clinically prescribed for non-small cell lung cancer and breast cancer. Here we studied the mechanism for vinorelbine-induced apoptosis in a human T-cell lymphoma. Although vinorelbine induces DNA fragmentation that is inhibited by specific peptide inhibitors for caspases-9 and -3 in Jurkat cells, caspase-8 deficiency retards vinorelbine-induced apoptosis. Activation of caspase-8 is also observed in vinorelbine-treated cells, and the activity is diminished when the caspase-3 activity is blocked by a specific peptide inhibitor, Ac-DNLC-CHO. Blocking of the Fas receptor with an antagonistic anti-Fas antibody does not affect vinorelbine-induced DNA fragmentation. These results suggest that vinorelbine-induced apoptosis is enhanced by the activation of caspase-8 via caspase-9-mediated activation of caspase-3, but not through a Fas-triggered signal. Western blotting suggests that vinorelbine cleaves caspase-3, -9 and -8 and reduces the amount of mitochondrial cytochrome c. Caspase-8 deficiency suppresses all of these events. A downstream substrate for caspase-8, Bid, is also cleaved in vinorelbine-treated cells, but the Bid truncation is also observed in caspase-8-deficient Jurkat cells. Importantly, recombinant caspases-3 and -9, as well as caspase-8, directly cleaves recombinant Bid in vitro. These results suggest that caspases-3 and -9 participate in Bid truncation, indicating a new mechanism for vinorelbine-induces apoptosis.
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PMID:Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis. 1829 1

Triple Negative Breast Cancer (TNBC) is an aggressive neoplasia with median Overall Survival (OS) less than two years. Despite the availability of new drugs, the chance of survival of these patients did not increase. The combination of low doses of drugs in a metronomic schedule showed efficacy in clinical trials, exhibiting an anti-proliferative and anti-tumour activity. In Victor-2 study we recently evaluated a new metronomic combination (mCHT) of Capecitabine (CAPE) and Vinorelbine (VNR) in breast cancer patients showing a disease control rate with a median Progression-Free Survival (PFS) of 4.7 months in 28 TNBC patients. Here in Victor-0 study, we examined the effect of mCHT vs standard (STD) schedule of administration of different combinations of 5-Fluorouracil (5FU), the active metabolite of CAPE, and VNR in TNBC cell lines MDA-MB-231 and BT-549. A significant anti-proliferative activity was observed in cells treated with metronomic vs STD administration of 5FU or VNR alone. Combination of the two drugs showed an additive inhibitor effect on cell growth in both cell lines. Moreover, after exposure of cells to 5FU and VNR under mCHT or conventional schedule of administration we also observed a downregulation of chemoresistance factor Bcl-2, changes in pro-apoptotic protein Bax and in cleaved effector caspase-3 and increased expression of LC3A/B autophagy protein. Our results therefore suggest that molecular mechanisms implicated in apoptosis and autophagy as well as the cross-talk between these two forms of cell death in MDA-MB-231 and BT-549 cells treated with 5FU and VNR is dose- and schedule-dependent and provide some insights about the roles of autophagy and senescence in 5FU/VNR-induced cell death.
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PMID:Metronomic combination of Vinorelbine and 5Fluorouracil is able to inhibit triple-negative breast cancer cells. Results from the proof-of-concept VICTOR-0 study. 2993 97