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)

Multiple genetic aberrations in human gliomas contribute to their highly infiltrative and rapid growth characteristics. Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival. We hypothesized that inhibiting the phosphorylation of FAK and IGF-IR by NVP-TAE226 (hereafter called TAE226), a novel dual tyrosine kinase inhibitor of FAK and IGF-IR, would suppress the growth and invasion of glioma cells. In culture, TAE226 inhibited extracellular matrix-induced autophosphorylation of FAK (Tyr(397)). TAE226 also inhibited IGF-I-induced phosphorylation of IGF-IR and activity of its downstream target genes such as MAPK and Akt. TAE226 retarded tumor cell growth as assessed by a cell viability assay and attenuated G(2)-M cell cycle progression associated with a decrease in cyclin B1 and phosphorylated cdc2 (Tyr(15)) protein expression. TAE226 treatment inhibited tumor cell invasion by at least 50% compared with the control in an in vitro Matrigel invasion assay. Interestingly, TAE226 treatment of tumor cells containing wild-type p53 mainly exhibited G(2)-M arrest, whereas tumor cells bearing mutant p53 underwent apoptosis. Induction of apoptosis by TAE226 was substantiated by detection of caspase-3/7 activation and poly(ADP-ribose) polymerase cleavage and by an Annexin V apoptosis assay. More importantly, TAE226 treatment significantly increased the survival rate of animals in an intracranial glioma xenograft model. Collectively, these data show that blocking the signaling pathways of FAK and IGF-IR with TAE226 has the potential to be an efficacious treatment for human gliomas.
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PMID:Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. 1743 Nov 14

Oxaliplatin is an efficient chemotherapeutic agent used for the treatment of metastatic human colon cancer, but cancer cells are frequently resistant. The aim of this study was to analyse the underlying mechanisms in a panel of 10 human colorectal cancer cell lines submitted to a short (2h) oxaliplatin treatment period, accordingly to the usual therapeutic procedure in humans. Sensitivity to oxaliplatin was a characteristic of p53 wild-type colon cancer cells. In contrast, all p53-mutated cell lines had a high IC50 to oxaliplatin, with the exception of the V9P cell line. Exposure to oxaliplatin resulted in G0/G1 arrest in p53 wild-type cell lines, and in S phase in p53-mutated cell lines. In our treatment conditions, no DNA accumulation in sub G0/G1 phase, no caspase-3 activation nor PARP cleavage were detected after oxaliplatin treatment, except for the V9P cell line. The major role of the p53-p21 pathway in oxaliplatin sensitivity was confirmed in the p53 wild-type HCT116 cell line, using siRNA duplex, and knockdown of the TAp73 protein also enhanced resistance to oxaliplatin in this cell line. Surprisingly, siRNA duplex invalidation revealed a residual effect of the mutant p53 protein in p53-mutated cell lines. Persistent sensitivity to oxaliplatin of the p53-mutated V9P cell line was associated with oxalipatin-induced apoptosis but TAp73 was not the responsible alternative pathway.
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PMID:p53 dependent and independent sensitivity to oxaliplatin of colon cancer cells. 1755 11

Cinnamaldehyde (Cin) has been shown to be effective in inducing apoptotic cell death in a number of human cancer cells. The aim of this study was to investigate the effect of pifithrin-alpha (PFTalpha; a specific p53 inhibitor) and mitogen-activated protein kinases (MAPKs) inhibitors [namely SP600125 (a specific JNK inhibitor), SB203580 (a specific p38 inhibitor) and PD98059 (a specific ERK inhibitor)] on apoptotic signaling transduction mechanism induced by Cin in human hepatoma PLC/PRF/5 (CD95-negative) cells. Using XTT assay, Cin exhibited a powerful cytotoxic effect and apoptotic induction in PLC/PRF/5 cells. Apoptosis was elicited when cells were treated with 1 microM Cin as characterized by morphological changes and the appearance of phosphatidylserine on the outer surface of the plasma membrane. Cin down-regulated the expression of Bcl-(XL), up-regulated mutant p53 and Bax proteins and promoted caspase-3 to active forms, as well as cleaving poly (ADP-ribose) polymerase (PARP) in a time-dependent pattern. This could be supported by the activation and phosphorylation of MAPKs, including JNK, ERK and p38 kinases. Pre-incubation with PFTalpha and specific MAPK inhibitors significantly diminished the effect of Cin-induced apoptosis. The activities of anti-apoptotic (Bcl-(XL)) and pro-apoptotic (Bax) proteins were remarkably affected by PFTalpha and PD98059 pre-treatment. PFTalpha effectively blocked PARP cleavage in cells treated with Cin, and also markedly prevented the phosphorylation of JNK, p38 and ERK proteins. These results suggest that p53 induction and MAPK signaling pathways are required for Cin-mediated apoptosis in PLC/PRF/5 cells.
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PMID:MAPK inhibitors and pifithrin-alpha block cinnamaldehyde-induced apoptosis in human PLC/PRF/5 cells. 1767 46

Mutations in the tumor suppressor p53 are detectable in over 50% of all human malignancies. Mutant p53 protein is incapable of transactivating its downstream target genes that are required for DNA repair and apoptosis. Chronic exposure to UVB induces p53 mutations and is carcinogenic in both murine and human skin. CP-31398, a styrylquinazoline compound, restores the tumor suppressor functions of mutant forms of p53 in tumor cells. However, its effectiveness in vivo remains unclear. Here, we demonstrate that CP-31398 blocked UVB-induced skin carcinogenesis and was associated with increases in p53, p21, and BclXs. CP-31398 downregulated Bcl2, proliferating nuclear cell antigen, and cyclin D1. Activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase also occurred in both tumor and perilesional skin following treatment. CP-31398 induced the expression of p53-dependent target proteins, and this was followed by apoptosis in UVB-irradiated wild-type mice but not in their p53-deficient littermates. Similar effects were observed in human skin carcinoma A431 cells expressing mutant p53. In addition, CP-31398 induced mitochondrial translocation of p53, leading to changes in mitochondrial membrane permeability pore transition (MPT) and consequent cytochrome c release in these cells. Blocking MPT diminished p53 translocation and apoptosis. These studies indicate that reconstituting p53 tumor suppressor functions in vivo by small molecular weight compounds may block the pathogenesis and progression of skin cancer.
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PMID:CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. 1806 27

In the present article, we describe a mechanistic study of a novel derivative of N-amidino-substituted benzimidazo[1,2-alpha]quinoline in two human colorectal cancer cell lines differing in p53 gene status. We used a proteomic approach based on two-dimensional gel electrophoresis coupled with mass spectrometry to complement the results obtained by common molecular biology methods for analyzing cell proliferation, cell cycle, and apoptosis. Tested quinoline derivative inhibited colon cancer cell growth, whereby p53 gene status seemed to be critical for its differential response patterns. DNA damage and oxidative stress are likely to be the common triggers of molecular events underlying its antiproliferative effects. In HCT 116 (wild-type p53), this compound induced a p53-dependent response resulting in accumulation of the G(1)- and S-phase cells and induction of apoptosis via both caspase-3-dependent and caspase-independent pathways. Quinoline derivative triggered transient, p53-independent G(2)-M arrest in mutant p53 cells (SW620) and succeeding mitotic transition, whereby these cells underwent cell death probably due to aberrant mitosis (mitotic catastrophe). Proteomic approach used in this study proved to be a valuable tool for investigating cancer cell response to newly synthesized compound, as it specifically unraveled some molecular changes that would not have been otherwise detected (e.g., up-regulation of the p53-dependent chemotherapeutic response marker maspin in HCT 116 and impairment in ribosome biogenesis in SW620). Finally, antiproliferative effects of tested quinoline derivative on SW620 cells strongly support its possible role as an antimetastatic agent and encourage further in vivo studies on the chemotherapeutic potential of this compound against colorectal carcinoma.
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PMID:Differential antiproliferative mechanisms of novel derivative of benzimidazo[1,2-alpha]quinoline in colon cancer cells depending on their p53 status. 1864 22

p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1(MET) reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1(MET) induces mutant p53-dependent mitochondria-mediated apoptosis through activation of caspase-2 with subsequent cytochrome c release and further activation of downstream caspase-9 and caspase-3. Inhibition of caspase-2 by a selective inhibitor and/or siRNA prevents cytochrome c release on PRIMA-1(MET) treatment and causes a significant reduction in PRIMA-1(MET)-induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1(MET) that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1(MET)-based anticancer drugs.
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PMID:PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. 1866 59

p53 mutations occur in a large number of human malignancies. Mutant p53 is unable to affect downstream genes necessary for DNA repair, cell cycle regulation, and apoptosis. The styrylquinazoline CP-31398 can rescue destabilized mutant p53 expression and promote activity of wild-type p53. The present study examines chemopreventive effects of CP-31398 on intestinal adenoma development in an animal model of familial adenomatous polyposis. Effects were examined at both early and late stages of adenoma formation. Effects of CP-31398 on early-stage adenomas were determined by feeding 7-week-old female C57BL/6J-APC(min) (heterozygous) and wild-type C57BL/6J mice with American Institute of Nutrition-76A diets containing 0, 100, or 200 ppm of CP-31398 for 75 days. To examine activity toward late-stage adenomas, CP-31398 administration was delayed until 15 weeks of age and continued for 50 days. During early-stage intervention, dietary CP-31398 suppressed development of intestinal tumors by 36% (P < 0.001) and 75% (P < 0.0001), at low and high dose, respectively. During late-stage intervention, CP-31398 also significantly suppressed intestinal polyp formation, albeit to a lesser extent than observed with early intervention. Adenomas in treated mice showed increased apoptotic cell death and decreased proliferation in conjunction with increased expression of p53, p21(WAF1/CIP), cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. These observations show for the first time that the p53-modulating agent CP-31398 possesses significant chemopreventive activity in vivo against intestinal neoplastic lesions in genetically predisposed APC(min/+) mice. Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation.
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PMID:Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator, in APCmin/+ mice. 1879 56

Prostate cancer has its highest incidence in the USA and is becoming a major concern in Asian countries. Bufadienolides are extracts of toxic glands from toads and are used as anticancer agents, mainly on leukemia cells. In the present study, the antiproliferative and apoptotic mechanisms of bufalin and cinobufagin on prostate cancer cells were investigated. Proliferation of LNCaP, DU145, and PC3 cells was measured by 3-(4,5-dimethylthiazol-2-yle)-2,5-diphenyltetrazolium bromide assay and the doubling time (tD) was calculated. Bufalin and cinobufagin caused changes in the tD of three prostate cancer cell lines, which were more significant than that of human mesangial cells. In addition, bufadienolides induced prostate cancer cell apoptosis more significantly than that in breast epithelial cell lines. After treatment, the caspase-3 activity and protein expression of caspase-3, -8, and -9 were elevated. The expression of other apoptotic modulators, including mitochondrial Bax and cytosolic cytochrome c, were also increased. However, expression of p53 was only enhanced in LNCaP cells. Downregulation of p53 by antisense TP53 restored the cell viability suppressed by bufalienolides. Furthermore, the increased expression of Fas was more significant in DU145 and PC3 cells with mutant p53 than in LNCaP cells. Transfection of Fas small interfering RNA restored cell viability in the bufadienolide-treated cells. These results suggest that bufalin and cinobufagin suppress cell proliferation and cause apoptosis in prostate cancer cells via a sequence of apoptotic modulators, including Bax, cytochrome c, and caspases. The upstream mediators might be p53 and Fas in androgen-dependent LNCaP cells and Fas in androgen-independent DU145 and PC3 cells.
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PMID:Apoptotic signaling in bufalin- and cinobufagin-treated androgen-dependent and -independent human prostate cancer cells. 1903 92

We analysed the effects of small interfering RNA (siRNA)-mediated silencing of Apollon, a member of the inhibitors of apoptosis protein family, on the proliferative potential and ability of human breast cancer cell lines to undergo apoptosis. In wild-type p53 ZR75.1 cells, Apollon knockdown resulted in a marked, time-dependent decline of cell growth and an increased rate of apoptosis, which was associated with p53 stabilisation and activation of the mitochondrial-dependent apoptotic pathway. Pre-incubation of cells with a p53-specific siRNA resulted in a partial rescue of cell growth inhibition, as well as in a marked reduction of the apoptotic response, indicating p53 as a major player in cell growth impairment consequent on Apollon silencing. Apollon knockdown induced consistently less pronounced anti-proliferative and pro-apoptotic effects in mutant p53 MDA-MB-231 cells than in ZR75.1 cells. Furthermore, the activation of caspase-3 seemed to be essential for the induction of apoptosis after Apollon knockdown, as the Apollon-specific siRNA had no effect on the viability of caspase-3-deficient, wild-type p53 MCF-7 cells or the ZR75.1 cells after RNA interference-mediated caspase-3 silencing. Our results indicate that p53 stabilisation and caspase-3 activation concur to determine the apoptotic response mediated by Apollon knockdown in breast cancer cells, and suggest Apollon to be a potential new therapeutic target for this malignancy.
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PMID:Apollon gene silencing induces apoptosis in breast cancer cells through p53 stabilisation and caspase-3 activation. 1922 5

Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNA-Pt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Bcl-2, FAP-1, Fas, FasL, TRAIL, Puma, Caspase-10, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells.
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PMID:Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. 1957 56


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