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)

We previously reported (UroOncology 1:165, 2001) cross-resistance and collateral-sensitivity to 2-chlorodeoxyadenosine (CldAdo) and fludarabine (FaraA), respectively, in a human renal cell carcinoma selected for resistance to 2'-deoxytubercidin (Caki-dTub). Insofar that these drugs generally demonstrate cross resistance rather than collateral sensitivity, we further examined the bases for this phenomenon. Both CldAdo and FaraA induce apoptosis, as the triphosphates, via binding to Apaf-1. In the presence of cytochrome c, this binding leads to activation of procaspase 9 to active caspase 9 that induces apoptosis through its activation of caspase 3. CldAdo and FaraA induced caspase 3 activities in wild type and Caki-dTub cell lines in a dose-dependent manner that paralleled the cross-resistance (CldAdo, 200-fold) or collateral sensitivity (FaraA, 20-fold) with regard to cell viability. The activation of caspase 3 was inhibited by the caspase 9 inhibitor, Z-LEHD-FMK, suggesting that both drugs act via the same pathway. By differential display and direct enzyme analysis, dihydrodiol dehydrogenase (DDH) was observed to be profoundly underexpressed in the Caki-dTub compared to wild-type Caki-1 cells. Stable transfection of the Caki-dTub cells with a vector encoding the enzyme led to partial reversal of the resistance to CldAdo. Resistance to cisplatin has recently been ascribed to overexpression of DDH in a human ovarian carcinoma cell line (Deng et al. in J Biol Chem 227:15035, 2002). It is tempting to speculate a mutation in the Apaf-1 nucleotide binding site that reduces (CldAdo) or increases (FaraA) toxicity in the Caki-dTub cells; however, the recent finding by others in a human ovarian carcinoma cell line suggests that DDH expression mediates the cross-resistance and perhaps, collateral-sensitivity.
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PMID:Dihydrodiol dehydrogenase in drug resistance and sensitivity of human carcinomas. 1700 30

One of the mechanisms of cisplatin cell cytotoxicity is the mitochondria-associated induction of apoptosis. The morphological or functional change of mitochondria in cisplatin-resistant cells has already been reported. Herein we present additional data describing the mitochondrial genomic and functional changes in cisplatin- resistant cells. Cisplatin increased the level of apoptotic cells in cisplatin-sensitive human ovarian carcinoma OV 2008 and C13 cells by 3.90+/-1.01 (SD; N=3) (p<0.01)-fold and 2.03+/-0.20 (SD; N=3) (p<0.01)-fold compared to the basal apoptotic level. This indicates a lower level induction of apoptosis by 50% in cisplatin-resistant OV 2008/C13 *5.25 variant (C13) cells. In both cell types, cisplatin cytotoxicity is mostly inhibited by the caspase-9 inhibitor as well as the caspase-3 inhibitor, Ac-DEVD-CHO, suggesting that the mitochondrial downstream event was functioning well in both the C13 cells and in OV 2008 cells. Mitochondrial transmembrane potential (DeltaPsim) determined by flow cytometry using DiOC6-stained cells revealed a significant depolarization of C13 cells as compared to OV 2008 cells. Treatment of these cells with cisplatin or hydrogen peroxide induces complete mitochondrial DNA damage in OV 2008 cells, while only partial DNA-destruction is observed in C13 cells, strongly suggesting that mitochondria are resistant to cisplatin and oxidative stress response. Continuous oxygen consumption of these cells monitored by a multi-channel dissolved oxygen meter is 1.70-fold higher in OV 2008 cells than C13 cells and the oxygen consumption was decreased by 30% in C13 cells, suggesting mitochondrial respiratory malfunction in these cells. The hypothesis generated here is that mitochondrial DNA resistance to cisplatin and oxidative stress response might be one of the main characteristics concerning the lower level of apoptosis induced by cisplatin. However, the mechanism by which the mitochondrial DNA encoded molecule is involved in cisplatin resistance remains to be determined.
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PMID:Characterization of mitochondria in cisplatin-resistant human ovarian carcinoma cells. 1701 83

A new synthetic isothiocyanate (ITC) derivative, ethyl 4-isothiocyanatobutanoate (E-4IB), appeared to be an effective modulator of cellular proliferation and potent inducer of apoptosis. In cooperation with cisplatin, this compound exerted synergistic effects in human ovarian carcinoma A2780 cells. In the present study we investigated in more detail E4IB-sensitisation for cisplatin-induced apoptosis. Sequential administration of both cytostatic agents led to increased intracellular platinum accumulation, glutathione level depletion and mitochondrial membrane potential dissipation. These events were accompanied with poly (ADP-ribosyl) polymerase cleavage, stimulation of caspase-3 activity, upregulation of p53, FasL and Gadd45alpha, cyclin B1 downregulation and an increase in mitogen-activated protein kinases JNK, ERK and p38 phosphorylation as well as PI3K level alterations. The presented results might have implications for developing new strategies aimed at therapeutic benefit of natural or synthetic ITCs in cooperation with various anticancer drugs.
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PMID:Sensitisation for cisplatin-induced apoptosis by isothiocyanate E-4IB leads to signalling pathways alterations. 1706 Sep 35

Novel pentablock copolymers of poly(diethylaminoethylmethacrylate) (PDEAEM), poly(ethylene oxide) (PEO), and poly(propylene oxide) (PPO), (PDEAEM-b-PEO-b-PPO-b-PEO-b-PDEAEM), were synthesized as vectors for gene delivery, and were tested for their biocompatibility on SKOV3 (human ovarian carcinoma) and A431 (human epidermoid cancer) cell lines under different in vitro conditions using various assays to elucidate the mechanism of cell death. These copolymers form micelles in aqueous solutions and can be tuned for their cytotoxicity by tailoring the weight percentage of their cationic component, PDEAEM. Copolymers with higher PDEAEM content were found to be more cytotoxic, though their polyplexes were less toxic than the polycations alone. Pentablock copolymers displayed higher cell viability than commercially available ExGen 500 at similar N:P ratios. While cell death with ExGen was found to be accompanied by an early loss of cell membrane integrity, pentablock copolymers caused very little membrane leakage. Caspase-3/7 assay confirmed that none of these polymers induced apoptosis in the cells. These pentablock copolymers form thermo-reversible gels at physiological temperatures, thereby enabling controlled gene delivery. Toxicity of the polymer gels was tested using an agarose-matrix, simulating an in vivo tumor model where injected polyplex gels would dissolve to release polyplexes, diffusing through tumor mass to reach the target cells. Twenty five weight percent of copolymer gels were found to be nontoxic or mildly cytotoxic after 24 h incubation. Transfection efficiency of the copolymers was found to be critically correlated to cytotoxicity and depended on DNA dose, polymer concentration, and N:P ratios. Transgene expression obtained was comparable to that of ExGen, but ExGen exhibited greater cell death.
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PMID:Investigation of in vitro biocompatibility of novel pentablock copolymers for gene delivery. 1710 14

The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO(2))(tz)(2)], has been prepared in methanol solution by using 1,2,4-triazole, dibromoacetic acid, and NaOH. Treatment of the [Cu(CH(3)CN)(4)][PF(6)] acceptor with Na[HC(CO(2))(tz)(2)] or Na[HC(CO(2))[(pz(Me2))(2)] in the presence of the tris(hydroxymethyl)phosphine coligand in methanol/acetonitrile solutions produced unprecedented mononuclear copper(I) complexes of the [L(n)]Cu[P(CH(2)OH)(3)](2) (L(1), 2; L(2), 3) [(CH(3)CN)(2)Cu(P(CH(2)OH)(3))(2)]PF(6), 4. These compounds have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectral data. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. The results reported here indicate that all the complexes showed in vitro antitumor activity similar or better than that of cisplatin, the most used metal-based antitumor drug. In particular, [HC(CO(2))(pz(Me2))(2)]Cu[P(CH(2)OH)(3)](2), 3 showed IC(50) values markedly lower than the reference compound against all tumor cell lines. Chemosensitivity tests performed on cisplatin sensitive and resistant cell lines have demonstrated that all these Cu(I) complexes were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the reference drug. Flow cytometric analysis on 2008 human ovarian carcinoma cells revealed that complex 3, chosen as the best candidate, induced a marked enlargement of both cell size and granularity, and a significant increase in the fraction of G2/M cells that, differently from cisplatin, was not accompanied by the appearance of a relevant sub-G1 fraction. Besides, no evidence of caspase-3 activation was detected in cells treated with complex 3. We hypothesize that the cytotoxic activity of the new copper(I) complex may be correlated to its ability to trigger paraptosis, a nonapoptotic mechanism of cell death.
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PMID:Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand. 1714 61

A major obstacle in treatment of ovarian cancer is intrinsic or acquired drug resistance causing failure of chemotherapy followed by a poor clinical outcome. Drug resistance of ovarian carcinoma can be caused by dysregulation of cellular factors involved in regulation of apoptosis and DNA repair pathways. In this study, 73 ovarian carcinoma specimens obtained before and after chemotherapy were analysed by immunohistochemistry for expression of seven proteins playing an important role in regulation of DNA mismatch repair and apoptosis. The prognostic significance of these proteins in the meaning of overall and progression-free survival was evaluated in univariate and multivariate analysis. Bcl-xL, hMSH2, caspase-3, p21 and p53 displayed prognostic importance in univariate analysis. Furthermore, it was demonstrated that caspase-3 and p21 were also independent prognostic markers for both, overall and progression-free survival. In conclusion, these data indicate that analysis of proteins involved in DNA mismatch repair and apoptosis can be useful for prediction of clinical outcome in ovarian carcinoma patients.
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PMID:Expression of factors involved in regulation of DNA mismatch repair- and apoptosis pathways in ovarian cancer patients. 1727 26

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARgamma agonists inhibit the growth of many types of cancers. To our knowledge, the effect of PPARgamma agonist on ovarian tumors is not reported. In this study, we used two human ovarian carcinoma cell lines (ES-2 and PA-1) to examine the effects of the PPARgamma agonists troglitazone (TGZ) and ciglitazone (CGZ) on cell survival. CGZ and TGZ inhibited viability in a dose-dependent manner in both types of ovarian cancer cells. The agonists also decreased cellular proliferation in association with an increase in the number of cells arrested in the G0/G1 phase of the cell cycle. Moreover, they increased apoptosis while increasing caspase-3 activity. Incubation of both the cell lines with the PPARgamma agonists led to upregulated PPARgamma expression. This effect appeared to be PPARgamma independent because the PPARgamma antagonist GW9662 did not reverse it. Along with the induction of apoptosis in ovarian cancer cells, protein expression levels of p53 and Bax markedly increased in response to the PPARgamma agonists. Our results demonstrated that PPARgamma agonists inhibited the viability of human ovarian cancer cells, at least partly by inducing apoptosis. As a result, these agonists may serve as future drugs for the prevention and treatment of ovarian cancer.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines. 1731 61

Cisplatin is one of the primary drugs utilized in the treatment of ovarian cancer. However, despite the initial effectiveness of chemotherapy in suppressing this disease, drug resistance almost invariably develops and cures are relatively rare. While it is generally thought that only compounds of the cis geometry express antitumor activity, a number of transplatinum derivates have shown preclinical promise. The current work investigates the influence of transplanaramine (TPA) compounds of structure trans-[Pt (O(2)CR)(2) (L) (L')], (L=NH(3), L'=pyridine, quinoline, isoquinoline; L=L'=pyridine; R=H, CH(3), CH(2)OH, etc.) (with a focus on the contribution of the carboxylate leaving group to drug action) on growth and viability of A2780 human ovarian carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The compounds, as a class, induce cell death through caspase-dependent apoptosis, with activation of both caspase 3 and caspase 9 and concomitant PARP cleavage. The trans-platinum compounds tested show induction of p53 as well as time dependent gammaH2AX induction, consistent with the promotion of DNA lesions. trans-[Pt(O(2)CH)(2)(NH(3))(4-pic)] can be shown to promote significant DNA strand breaks and DNA interstrand cross-linking. The enhanced cytotoxicity of trans-[Pt(O(2)CH)(2)(NH(3))(4-pic)] compared to its isostructural -O(2)CCH(3) and -O(2)CCH(2)OH analogs may be a consequence of its accelerated cellular accumulation, increased hydrolytic activation, interstrand cross-linking and abortive efforts by the cell to repair the cross linked DNA.
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PMID:Promotion of DNA strand breaks, interstrand cross-links and apoptotic cell death in A2780 human ovarian cancer cells by transplatinum planar amine complexes. 1741 17

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

For the evaluation of novel therapies, and for initial in vitro testing of potential in vivo graft-versus-tumour-effects (GvT), cytotoxicity of effector cells against target tumour cells needs to be determined in a reliable fashion. Recently Zimmermann et al. [Zimmermann, S.Y., Esser, R., Rohrbach, E., Klingebiel, T., Koehl, U., 2005. A novel four-colour flow cytometric assay to determine natural killer cell or T-cell-mediated cellular cytotoxicity against leukaemia cells in peripheral or bone marrow specimens containing greater than 20% of normal cells. J. Immunol. Methods. 296(1-2), 63-76] introduced a single platform, no-wash flow cytometric assay to quantify natural killer (NK) cell cytotoxicity against leukaemia cells. Here we have optimised this method introducing a novel five-colour flow cytometric assay for the evaluation of NK cell activity against adherent tumour cells, in particular neuroblastoma cells (NB cells). Beside an enhanced cytotoxic activity corresponding to increasing effector/target (E:T) ratios, we could demonstrate an increasing cytotoxicity in a time-dependent manner over a time period of 8 h. The usefulness of this novel method was also confirmed with human tumour cells lines of various other origin including breast and ovarian carcinoma and Wilms tumour cells freshly isolated from a patient after surgery. In addition to flow cytometric analysis, we monitored NK-cell-mediated induction of target cell apoptosis via the caspase cascade in attacked NB cells by fluorescence microscopy after immunofluorescence staining of activated Caspase-3 (Casp-3) in combination with detection of CD45(+) and CD9(+) for discrimination between NK and NB cells. In summary, this novel flow cytometric cytotoxicity assay enables efficient quantification of the phenotype of both, effector and adherent target tumour cells, and therefore represents a useful tool for research on immunotherapies that rely on cytotoxic effector cells.
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PMID:A novel five-colour flow cytometric assay to determine NK cell cytotoxicity against neuroblastoma and other adherent tumour cells. 1766 91


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