UNIPROT:P10415 - FACTA Search

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

Cyclophosphamide (CPA), a widely used oxazaphosphorine anti-cancer prodrug, is inactive until it is metabolized by cytochrome P450 to yield phosphoramide mustard and acrolein, which alkylate DNA and proteins, respectively. Tumor cells transduced with the human cytochrome P450 gene CYP2B6 are greatly sensitized to CPA, however, the pathway of CPA-induced cell death is unknown. The present study investigates the cytotoxic events induced by CPA in 9L gliosarcoma cells retrovirally transduced with CYP2B6, or induced in wild-type 9L cells treated with mafosfamide (MFA) or 4-hydroperoxyifosfamide (4OOH-IFA), chemically activated forms of CPA and its isomer ifosfamide. CPA and MFA were both shown to effect tumor cell death by stimulating apoptosis, as evidenced by the induction of plasma membrane blebbing, DNA fragmentation, and cleavage of the caspase 3 and caspase 7 substrate poly(ADP-ribose) polymerase (PARP) in drug-treated cells. Caspase 9 was identified as the regulatory upstream caspase activated in 9L cells treated with CPA, MFA, or 4OOH-IFA, implicating the mitochondrial apoptotic pathway in oxazaphosphorine-induced tumor cell death. Correspondingly, expression of the mitochondrial proapoptotic factor Bax enhanced caspase 9 activation, plasma membrane blebbing, and drug-induced cytotoxicity. Conversely, overexpression of the mitochondrial antiapoptotic factor Bcl-2 blocked caspase 9 activation, leading to an inhibition of drug-induced plasma membrane permeability and blebbing, terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity, PARP cleavage, Annexin V positivity, and drug-induced cell death. Although Bcl-2 thus blocked the cytotoxic effects of activated CPA, it did not inhibit the drug's cytostatic effects. CPA induced S-phase cell cycle arrest followed by conversion to an apoptotic pre-G1 state in wild-type 9L cells; by contrast, Bcl-2-expressing 9L cells accumulated in G2/M in response to CPA treatment. Intratumoral expression of Bcl-2 and related family members, including both apoptotic and antiapoptotic factors, is thus an important determinant of the responsiveness of tumor cells to CPA and ifosfamide, both in the context of conventional chemotherapy and in patients sensitized to these oxazaphosphorine drugs by the use of cytochrome P450-based gene therapy.
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PMID:Cyclophosphamide induces caspase 9-dependent apoptosis in 9L tumor cells. 1172 34

Selective A3 adenosine receptor agonists have been shown to induce apoptosis in a variety of cell types. In this study we examined the effects of adenosine receptor agonists selective for A1, A2A, or A3 receptors on the induction of apoptosis in primary cultures of rat astrocytes and in C6 glial cells. Treatment of the cells with the A3 receptor agonist Cl-IB-MECA (10 microM) induced apoptosis in both cell types. The effects of Cl-IB-MECA were partially antagonized by the A3 receptor-selective antagonist MRS 1191. In contrast, the A1 and A2A receptor agonists, CPA and CGS 21680, respectively, did not have significant effects on apoptosis in these cells. Cl-IB-MECA reduced the expression of endogenous Bcl-2, whereas it did not affect the expression of Bax. Overexpression of Bcl-2 in C6 cells abrogated the induction of apoptosis induced by the A3 agonist. Cl-IB-MECA also induced an increase in caspase 3 activity and caspase inhibitors decreased the apoptosis induced by the A3 agonist. These findings suggest that intense activation of the A3 receptor is pro-apoptotic in glial cells via bcl2 and caspase-3 dependent pathways.
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PMID:Roles of BCL-2 and caspase 3 in the adenosine A3 receptor-induced apoptosis. 1185 24

The main objectives of this study were to determine the feasibility of administering high doses of cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) every 14-21 days to patients with follicular small cleaved cell lymphoma. For each patient, the treatment was not considered feasible if fewer than four cycles of cyclophosphamide chemotherapy could be administered on schedule (i.e. at least every 29 days) or (1) hospitalization of the patient for longer than three days was necessary for neutropenic fever (38 degrees C) or bacteriologically documented infection in > 50% of the cycles, or (2) grade > or = 2 hemorrhage in association with thrombocytopenia of grade > or = 3 severity occurred in > 50% of the cycles or (3) non-hematologic toxicity (excluding nausea/vomiting and alopecia) of grade > or = 3 occurred in > 50% of cycles. The goal was to have a treatment program feasible in 75% or more of the treated patients. The secondary objectives were to determine the toxicities, the complete and partial response rates, and the time to treatment failure (TTF). The trial also attempted to assess the effectiveness of this treatment program in eradicating Bcl-2 rearrangements by PCR, and to assess complete remission duration in relationship to PCR results in patients who respond to this chemotherapy program. Patients were required to have histologically documented non-Hodgkin's lymphoma of the subtypes follicular, predominantly small cleaved cell (IWF-B) or follicular mixed, (IWF-C). Patients were required to have Stage IV disease including histologic evidence of bone marrow involvement. Measurable disease was required and patients were also required to have one of the following risk factors: > or = 2 extranodal sites, node or nodal group > or = 5 cm. Submission of fresh bone marrow for molecular genetic studies for the presence of Bcl-2-Ig fusion DNA was mandatory in previously untreated patients. Patients had to be between 18 and physiologic age 55 years (carefully selected patients over age 55 years were also eligible), expected survival > 2 years, performance status 0-1, and have adequate renal, hepatic and bone marrow function, and a cardiac ejection fraction > or = 50%. Cyclophosphamide 4.5 g/m2 i.v. was given with mesna every 14 days with rhG-CSF support. Twenty-nine patients were accrued to this trial. The median follow-up time is 5.0 years, with a range of 2.5-6.7 years. The overall response rate was 75% (9 CRs 37.5%, 9PRs 37.5%). The median duration of survival is 5.53 years. The 1-year estimated probability of freedom from treatment failure was 50% and of survival at 1 year was 92%. No strong association was observed between TTF and age, symptomatic stage, histology performance status, number of extranodal sites or baseline Bcl-2 status. At 3 years the survival of all patients was 78% and failure free survival was 17%. 15 (62%) of the 24 eligible previously untreated patients met the criteria for feasibility specified in the protocol. The 95% CI for the feasibility rate is (44 and 82%). Twenty-two of the 24 (92%) previously untreated patients had specimens submitted for testing for Bcl-2 rearrangements. Thirteen of the 22 (59%) were found to have rearrangements at baseline. Post-treatment specimens were submitted for seven of the 13 patients. Four of the seven converted to Bcl-2 negative following treatment. Eight of 13 Bcl-2 positive patients (62%) had a clinical response to treatment. The 95% exact binomial CI for the total response rate in this subgroup is (28 and 88%). This study demonstrates that repetitive doses of cyclophosphamide at 4.5 g/m2 every two weeks with rhG-CSF support can be administered to selected younger patients with advanced follicular lymphoma with morphologic involvement of the bone marrow with acceptable non-hematologic toxicity.
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PMID:High dose cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) in the treatment of follicular, low grade non-Hodgkin's lymphoma: CALGB 9150. 1191 6

In this study we use the N-substituted benzamides declopramide (3-CPA) and N-acetyl declopramide (Na-3-CPA) to investigate the involvement of the transcription factor NF-kappaB in the induction of apoptosis and surface immunoglobulin kappa (Igkappa) expression in the mouse pre-B cell line 70Z/3. We first showed that 3-CPA-induced apoptosis at doses around 500 microM and that the 3-CPA-induced apoptosis could be suppressed by over-expression of the Bcl-2 protein. Na-3-CPA was shown to be non-apoptotic at doses up to 1-2 mM. On the other hand, Na-3-CPA inhibited LPS-induced Igkappa expression while 3-CPA had no effect. Further analysis showed that while 3-CPA inhibited breakdown of IkappaBalpha, Na-3-CPA inhibited breakdown of IkappaBbeta. In addition, we used a 70Z/3 cell line expressing a dominant negative IkappaBalpha (70Z/3(deltaNIkappaBalpha)). The 70Z/3(deltaNIkappaBalpha) cell line was shown to be more sensitive to apoptosis and cytotoxicity induced by 3-CPA as well as by LPS, probably due to a defect in NF-kappaB rescue mechanism. Taken together, our data implicate distinct roles for IkappaBalpha and IkappaBbeta in regulating various NF-kappaB activities.
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PMID:Differential usage of IkappaBalpha and IkappaBbeta in regulation of apoptosis versus gene expression. 1253 63

Bcl-2 functions as a key survival factor for lymphocytes and is highly expressed in a majority of non-Hodgkin's lymphomas. The ability of oblimersen sodium (Genasense, previously known as G3139) to target bcl-2 messenger RNA and decrease Bcl-2 protein levels has the potential to enhance the activity of cytotoxic chemotherapy. Pretreatment with oblimersen followed by cyclophosphamide (Cytoxan, Neosar) markedly improved survival relative to single-agent cyclophosphamide in a murine xenograft model. Oblimersen has also enhanced the cytotoxicity of a variety of other agents against non-Hodgkin's lymphoma, including etoposide, rituximab (Rituxan), and alemtuzumab (Campath). An initial phase I study of oblimersen in non-Hodgkin's lymphoma demonstrated modest single-agent activity. Recent reports suggest that oblimersen may add to the activity of R-CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone) in previously untreated mantle cell lymphoma and to rituximab alone in a variety of subtypes of relapsed non-Hodgkin's lymphoma. Additional studies in both treatment-naive and relapsed patients will define the role of oblimersen in the treatment of non-Hodgkin's lymphoma.
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PMID:Targeting the proapoptotic factor Bcl-2 in non-Hodgkin's lymphoma. 1565 Nov 74

Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 microg/ml), the IC50 value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.
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PMID:Doxycycline potentiates antitumor effect of cyclophosphamide in mice. 1566 32

Cardiotoxin III (CTX III) is a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom. This is the first report on the mechanism of the anticancer effect of CTX III in human colorectal cancer Colo205 cells. 2. Cardiotoxin III-induced Colo205 cell apoptosis was confirmed by DNA fragmentation (DNA ladder and sub-G1 formation) with an IC(50) of 4 mg/mL at 48 h. 3. Further mechanistic analysis demonstrate that CTX III induced the loss of mitochondrial membrane potential (Dym), cytochrome c release from mitochondria into the cytosol and activation of capase-9, caspase 3, as well as markedly enhancing the expression of Bax, but not Bcl-2, protein in the cells. Moreover, the CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. 4. However, CTX III did not generate the formation of reactive oxygen species and anti-oxidants, including N-acetylcysteine, and catalase could not block CTX III-induced apoptosis in the Colo205 cells. 5. Taken together, these results suggest that CTX III may induce apoptosis through a mitochondrial- and caspase-dependent mechanism and alteration of Bax/Bcl-2 ratio in human colorectal Colo205 cancer cells.
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PMID:Mechanisms of cardiotoxin lll-induced apoptosis in human colorectal cancer colo205 cells. 1648 59

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III-induced K562 cell apoptosis was confirmed by DNA fragmentation (DNA ladder, sub-G1 formation) and phosphatidylserine (PS) externalization with an IC(50) value of 1.7 microg/ml at 48 h. A mechanistic analysis demonstrated that CTX III-induced apoptotic cell death was accompanied by up-regulation of both Bax and endonuclease G (Endo G), and downregulation of Bcl-X(L). CTX III had no effect on the levels of Bcl-2, Bid, XIAP survivin, and AIF proteins. CTX III treatment caused loss of the mitochondrial membrane potential (DeltaPsim), release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and -3. CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK. However, CTX III did not generate reactive oxygen species (ROS) and antioxidants, including N-acetylcysteine and catalase, did not block CTX III-induced apoptosis in K562 cells. Modulation of Bax, Bcl-XL, and the Endo G proteins, release of mitochondrial cytochome c, and activation of caspase-3 and -9 all are involved in the CTX III-triggered apoptotic process in human leukemia K562 cells.
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PMID:Up-regulation of Bax and endonuclease G, and down-modulation of Bcl-XL involved in cardiotoxin III-induced apoptosis in K562 cells. 1695 23

Cardiotoxin III (CTX III) is a basic polypeptide of 60-amino acid residues isolated from Naja naja atra venom, exerts its anti-proliferative activity in human leukemia K562 cells. In the present study, the expression of mRNAs and proteins related to cell cycle and apoptosis in human leukemia K562 cells induced by CTX III was investigated by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Flow cytometric analysis revealed that CTX III resulted in G2/M phase arrest in the cell cycle progression, which was associated with a marked decrease in the mRNA and protein expressions of cyclin A, cyclin B1, and Cdk 2, with no detectable changes in the levels of Cdk 1, cyclin D1, and cyclin E. Moreover, the increase in apoptosis was associated with the Bax gene and protein levels significantly increased as treatment durations of CTX III increased, while the Bcl-2 mRNA and protein levels exhibited no changes. We also observed that caspase-9 and caspase-3 genes remained unchanged up to 12 h with 2 microg/ml CTX III. These molecular alterations provide an insight into CTX III-caused growth inhibition, G2/M arrest, and apoptotic death of K562 cells.
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PMID:Effects of cardiotoxin III on expression of genes and proteins related to G2/M arrest and apoptosis in K562 cells. 1714 43

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. The molecular effects of CTX III on HL-60 cells were dissected in the present study. We found that the antiproliferative action of CTX III on HL-60 cells was mediated through apoptosis, as characterized by an increase of sub G1 population, DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage. Upregulation of Bax, downregulation of Bcl-2, the release of mitochondrial cytochrome c to cytosol and the activations of capase-9 and -3 were noted, while CTX III had no appreciable effect on the levels of Bcl-X(L) and Bad proteins. Moreover, c-Jun N-terminal kinase (JNK) was activated shortly after CTX III treatment in HL-60 cells. Consistently, the SP600125 compound, an anthrapyrazolone inhibitor of JNK, suppressed apoptosis induced by CTX III. As expected, this JNK inhibitor also attenuated the modulation of Bax and Bcl-2, as well as the cytosolic appearance of cytochrome c and the activation of caspase-3 and caspase-9 that induced by CTX III. These findings suggest that CTX III can induce apoptosis in HL-60 cells via the mitochondrial caspase cascade and the activation of JNK is critical for the initiation of the apoptotic death of HL-60 cells.
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PMID:Cardiotoxin III induces c-jun N-terminal kinase-dependent apoptosis in HL-60 human leukaemia cells. 1751 39

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