Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of in vitro inhibition of tumor cell growth, IFNs have been generally considered to be antiproliferative proteins. To probe further the potential mechanisms of the antitumor effects of IFNs, we have assessed apoptosis in response to IFN-alpha2 and IFN-beta in cell lines of varied histologies, with a focus on melanomas. Many of the cell lines tested underwent apoptosis in response to IFN-beta, as assessed both by Annexin V and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. In general, IFN-beta had greater growth inhibitory and proapoptotic effects than IFN-alpha2 on all cell lines. The melanoma cell line WM9, sensitive to growth inhibition by IFNs, had a greater degree of apoptosis than A375 melanoma cells, which were largely resistant to antigrowth effects of IFNs. IFN-beta-induced apoptosis was dependent on activation of the caspase cascade with cleavage of caspases 3, 8, and 9 and of the caspase 3 substrate, poly(ADP-ribose) polymerase. Caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl keton or benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl keton, inhibited IFN-beta-induced apoptosis. Other changes associated with apoptosis, including the movement of cytochrome c from mitochondria to cytoplasm and DNA fragmentation, were also identified in response to IFN-beta. Apo2L ligand [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)] was one of the early genes induced by IFN-beta in apoptosis-sensitive WM9 cells. Other sensitive melanoma cell lines had a similar IFN-beta-specific induction of TRAIL. Neutralizing antibody to TRAIL inhibited IFN-beta-induced apoptosis in WM9 cells. In resistant A375 cells, IFN-beta did not induce TRAIL/Apo2L expression. Thus, induction of TRAIL by IFNs in some tumor types may initiate the apoptotic cascade. This study offers another mechanism for the antitumor effects of IFNs.
Clin Cancer Res 2001 Jun
PMID:Preferential induction of apoptosis by interferon (IFN)-beta compared with IFN-alpha2: correlation with TRAIL/Apo2L induction in melanoma cell lines. 1141 May 25

Expression of the DNA repair and recombination protein human Rad51 (HsRad51) is increased in transformed cells and in cancer cell lines. In order to study the effects of acute HsRad51 ectopic overexpression on cell proliferation, cell cycle progression, and apoptosis, we generated clones of the human fibrosarcoma cell line HT1080 carrying a HsRad51 transgene under a repressible promoter. The HsRad51-overexpressing cells showed decreased plating efficiency and growth rate in a dose-dependent manner with regard to the degree of overexpression. An accumulation of HsRad51-overexpressing cells in G(2) was observed following release of cells after synchronization with double thymidine block. Moreover, the fraction of apoptotic cells measured by annexin V-FACS increased with the time of HsRad51 overexpression. In the light of these observations, sustained increased levels of HsRad51 may contribute to tumor progression by causing a selection for cells tolerant to the growth-suppressive and apoptosis-inducing effects of acute HsRad51 overexpression.
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PMID:Effects of HsRad51 overexpression on cell proliferation, cell cycle progression, and apoptosis. 1146 Nov 18

TP53 is the most commonly altered tumor-suppressor gene in cancer and is currently being tested in Phase II/III gene replacement trials. Many tumors contain wild-type TP53 sequence with elevated MDM2 protein levels, targeting p53 for degradation. These tumors are more refractory to treatment with exogenous wild-type p53. Here we generate a recombinant adenovirus expressing a p53 variant, rAd-p53 (d 13-19), that is deleted for the amino acid sequence necessary for MDM2 binding (amino acids 13-19). We compared the apoptotic activity of rAd-p53 (d 13-19) with that of a recombinant adenovirus expressing wild-type p53 (rAd-p53) in cell lines that differ in endogenous p53 status. rAd-p53 (d 13-19) caused higher levels of apoptosis in p53 wild-type tumor lines compared with wild-type p53 treatment, as measured by annexin V-FITC staining. In p53-altered tumor lines, rAd-p53 (d 13-19) showed apoptotic activity similar to that seen with wild-type p53 treatment. In normal cells, no increase in cytopathicity was detected with rAd-p53 (d 13-19) compared with wild-type p53 treatment. This variant protein displayed synergy with chemotherapeutic agents to inhibit proliferation of ovarian and breast cell lines. The p53 variant showed greater antitumor activity in an established p53 wild-type tumor compared with treatment with wild-type p53. The p53 variant represents a means of expanding TP53 gene therapy to tumors that are resistant to p53 treatment due to the cellular responses to wild-type p53.
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PMID:Enhanced apoptotic activity of a p53 variant in tumors resistant to wild-type p53 treatment. 1147

MMP inhibitors are used clinically for the stabilization of tumor growth, thus prolonging survival in cancer patients. However, their role in the treatment of hematopoietic malignancies remains unclear. In the present study, we investigated the effects of a new MMP inhibitor, SI-27, in hematopoietic malignancies. SI-27 alone induces apoptosis in several human myeloid leukemia cell lines such as U937, NB4, and HL60 cells by activating caspase 8, 9, and 3. Apoptosis was measured with annexin V positive staining, a drop in mitochondrial transmembrane potential (deltapsim), presence of hypodiploid DNA, and cleavage of PARP and IkappaBalpha. Furthermore, at lowered concentrations, which did not directly induce apoptosis, SI-27 acted to sensitize U937 cells and other cells to tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis. The accumulation of membrane Fas, the Fas ligand, and TNFR1 were not apparent due to exposure to SI-27, and antagonistic anti-Fas or anti-Fas ligand antibodies did not block SI-27-induced apoptosis. Thus, SI-27-induced apoptosis is not mediated by the Fas pathway. These results suggest that MMP inhibitors, alone or in combination with other cytotoxic agents, can provide a unique method for treating acute myeloid leukemia, refractory to classical anti-cancer drugs, and may thus suppress recurrence.
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PMID:A new matrix metalloproteinase inhibitor SI-27 induces apoptosis in several human myeloid leukemia cell lines and enhances sensitivity to TNF alpha-induced apoptosis. 1148 May 63

ZD2767P is a phenol mustard glutamate prodrug which is currently being developed for Antibody Directed Enzyme Prodrug Therapy (ADEPT). In ZD2767 ADEPT an active bi-functional alkylating drug, ZD2767D (4-[N,N-bis(2-iodoethyl)amino]phenol), is generated following cleavage of ZD2767P by the bacterial enzyme carboxypeptidase G2 (CPG2) which is targeted to the tumour by conjugation to the F(ab')(2)fragment of the anti-CEA antibody A5B7. The aim of the studies described here was to identify the mode of cell death induced by ZD2767P + CPG2 in comparison to the established nitrogen mustard chlorambucil. The contribution of bifunctional and monofunctional ZD2767 DNA lesions to cell death induction was investigated using a monofunctional ZD2767D analogue. Apoptosis in LoVo tumour cells was studied by three different methods (nuclear morphology, annexin V staining and TUNEL). Levels of apoptosis detected using the three assays were similar, and each drug treatment produced apoptosis at levels above those in control cells at concentrations which resulted in tumour cell growth inhibition. The bi-functional compounds, ZD2767P + CPG2 and chlorambucil, induced apoptosis in a concentration and time dependent manner, with equitoxic concentrations producing equivalent levels of apoptosis. In contrast, the mono-functional ZD2767D analogue at 100 microM resulted in the maximal level of apoptosis at 25 h with no further increase over the following 72 h. These studies have demonstrated that apoptosis is the mechanism of cell death induced by the ZD2767 ADEPT system, and that levels of apoptosis produced by ZD2767 are similar to those observed at equitoxic concentrations of the classical nitrogen mustard chlorambucil. The mono-functional ZD2767 analogue also induced apoptosis, but with a different time course and characteristics. In conjunction with previous data, these studies have shown that the potent activity of ZD2767 can be attributed to the ability of the compound to induce bifunctional DNA lesions and engage apoptosis.
Br J Cancer 2001 Sep 01
PMID:Induction of apoptosis by the ADEPT agent ZD2767: comparison with the classical nitrogen mustard chlorambucil and a monofunctional ZD2767 analogue. 1153 Dec 65

The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G(2)/M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine- and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G(1)cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade.
Br J Cancer 2001 Sep 14
PMID:Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity. 1155 44

Apoptosis is involved in many biological processes, especially during chemotherapy in cancer patients. Chemotherapy is also associated with an increased risk of thrombosis. The relationship between thrombogenicity and apoptosis was studied in various human tumour cell lines and non-tumour cell lines. Apoptosis was induced by the chemotherapeutic agent camptothecin and by Fas ligand, then quantified by staining with fluorescein isothiocyanate-conjugated annexin V and propidium iodide. A significant correlation between thrombin generation and degree of apoptosis was observed (P < 0.0005). Addition of anti-tissue factor antibody in excess or of tissue factor pathway inhibitor partially inhibited thrombin generation, suggesting that tissue factor activation was responsible for this process. A statistical correlation between tissue factor activity and degree of apoptosis was also found (P < 0.005). Both thrombin generation and tissue factor activity were blocked by the addition of annexin V, which binds and inhibits phosphatidylserine. This indicates that the exteriorization and exposure of phosphatidylserine on the cell surface membrane during apoptosis were essential for both thrombin generation and tissue factor activation.
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PMID:Thrombogenic role of cells undergoing apoptosis. 1170 40

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

Cisplatin is a potent chemotherapeutic agent that is used to treat many human malignancies. Unfortunately, in addition to side effects such as ototoxicity, anaphylaxis, and bone marrow suppression, a significant percentage of patients receiving cisplatin develop severe nephrotoxicity. Mitochondrial dysfunction that is mediated via the generation of reactive oxygen species has been implicated in the pathogenesis of cisplatin-induced renal injury. To address the mechanism, it was hypothesized that overexpression of antioxidant enzymes, such as mitochondria-localized manganese superoxide dismutase (MnSOD) or mitochondria-targeted catalase (mito-Cat), would be cytoprotective in cisplatin-induced cell injury. To this end, human MnSOD or a mito-Cat vector were stably transfected into human embryonic kidney 293 cells. Cells that overexpressed MnSOD exhibited significantly less cell rounding and detachment compared with both mito-Cat and vector controls after exposure to 20 microM cisplatin. Cell injury as assessed by DNA fragmentation and annexin V binding assays was significantly decreased in the cells that overexpressed MnSOD compared with vector alone and mito-Cat. In addition, elevated levels of MnSOD were strongly associated with increased clonogenic potential after cisplatin challenge. Thus, overexpression of MnSOD, and not catalase, protects against cisplatin-induced renal epithelial cell injury. These results demonstrate the importance of reactive oxygen species in the mechanism that underlies cisplatin-induced renal injury and specifically implicate the superoxide radical, and not hydrogen peroxide, as the mediator.
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PMID:Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. 1172 37

We have reported previously that sigma-2 receptors are expressed in high densities in a variety of tumor cell types (B. J. Vilner et al., Cancer Res., 55: 408-413, 1995) and that various sigma ligands have cytotoxic effects (B. J. Vilner et al., J. Neurosci., 15: 117-134, 1995). Other investigators have demonstrated increased expression of sigma-2 receptors in rapidly proliferating tumors (R. H. Mach et al., Cancer Res., 57: 156-161, 1997) and the ability of some sigma ligands to inhibit proliferation (P. J. Brent and G. T. Pang, Eur. J. Pharmacol., 278: 151-160, 1995). We demonstrate here the ability of sigma-2 receptor agonists to induce cell death by a mechanism consistent with apoptosis. In breast tumor cell lines that are sensitive (MCF-7) and resistant (MCF-7/Adr-, T47D, and SKBr3) to antineoplastic agents, incubation with the sigma-2 subtype-selective agonists CB-64D and CB-184 produced dose-dependent cytotoxicity (measured by lactate dehydrogenase release into medium). The EC(50) for this response was similar across cell lines, irrespective of p53 genotype and drug-resistance phenotype. CB-64D and the subtype nonselective sigma-2 agonists haloperidol and reduced haloperidol induced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining in MCF-7 and T47D cells, indicating that cell death occurs via apoptosis. Apoptosis was also indicated by increases in Annexin V binding caused by CB-64D. In MCF-7 cells, cytotoxicity and Annexin V binding induced by the antineoplastics doxorubicin and actinomycin D was partially or completely abrogated by certain specific and general inhibitors of caspases. In contrast, caspase inhibitors had no effect on sigma-2 receptor-mediated (CB-64D and CB-184) cytotoxicity or Annexin V binding. Marked potentiation of cytotoxicity was observed when a subtoxic dose of CB-184 was combined with doxorubicin or actinomycin D, both in drug-sensitive (MCF-7) and drug-resistant (MCF-7/Adr-) cell lines. Haloperidol potentiated doxorubicin only in drug-resistant cells. These findings suggest the involvement of a novel p53- and caspase-independent apoptotic pathway used by sigma-2 receptors, which is distinct from mechanisms used by some DNA-damaging, antineoplastic agents and other apoptotic stimuli. These observations further suggest that sigma-2 receptors may be targets that can be therapeutically exploited in the treatment of both drug-sensitive and drug-resistant metastatic tumors.
Cancer Res 2002 Jan 01
PMID:Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. 1178 94


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