Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although isothiocyanates have been shown to inhibit carcinogen-induced tumorigenesis, no studies have been made to determine their therapeutic potential for the treatment of breast cancer. In the present study, we evaluated the apoptotic activities of phenethyl isothiocyanate (PEITC) in human breast cancer MCF-7 cells. Exposure to PEITC potently reduced cell viability. In addition, DNA fragments and TUNEL positive nuclei were detected in PEITC-treated cells. Furthermore, PEITC induced apoptosis via activation of caspases 7 and 9 and the cleavage of PARP, and these effects were reversed by treatment with the caspase inhibitor, Z-VAD-fmk. PEITC also caused a decrease in the levels of Bcl-2 with a concomitant increase in Bax levels, which resulted in the release of cytochrome c. XIAP suppression and Smac translocation also contributed to the PEITC-induced apoptosis. However, PEITC did not increase the expressions of p53 and p21. Taken together, the results of this study demonstrate that PEITC significantly induces apoptosis via a mitochondrial pathway. Specifically, PEITC induced a change in the Bax/Bcl-2 ratios, XIAP levels and Smac translocation that was conjunction with the release of cytochrome c and following caspase activation. Therefore, PEITC has the potential for use as a therapeutic agent for the treatment of breast cancer.
 ...
PMID:Phenethyl isothiocyanate induced apoptosis via down regulation of Bcl-2/XIAP and triggering of the mitochondrial pathway in MCF-7 cells. 1909 31

Hepatocellular carcinoma (HCC) is a major health problem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in human hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular alterations for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta (TGF-beta). Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counteracting apoptosis, such as Bcl-X(L), Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are up-regulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro-forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs pathways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evidence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.
 ...
PMID:Dysregulation of apoptosis in hepatocellular carcinoma cells. 1919 51

Physalis peruviana L. (PP) is a popular folk medicine used for treating cancer, leukemia, hepatitis, rheumatism and other diseases. In this study, our objectives were to examine the total flavonoid and phenol content of different PP extracts (aqueous: HWEPP; ethanolic: EEPP; supercritical carbon dioxide: SCEPP-0, SCEPP-4 and SCEPP-5) and their antiproliferative effects in human lung cancer H661 cells. Among all the extracts tested, results showed that SCEPP-5 possessed the highest total flavonoid (226.19 +/- 4.15 mg/g) and phenol (100.82 +/- 6.25 mg/g) contents. SCEPP-5 also demonstrated the most potent inhibitory effect on H661 cell proliferation. Using DNA ladder and flow cytometry analysis, SCEPP-5 effectively induced H661 cell apoptosis as demonstrated by the accumulation of Sub-G1 peak and fragmentation of DNA. SCEPP-5 not only induced cell cycle arrest at S phase, it also up-regulated the expression of pro-apoptotic protein (Bax) and down-regulated the inhibitor of apoptosis protein (IAP). Furthermore, the apoptotic induction in H661 cells was found to associate with an elevated p53 protein expression, cytochrome c release, caspase-3 activation and PARP cleavage. Taken together, these results conclude that SCEPP-5 induced cell cycle arrest at S phase, and its apoptotic induction could be mediated through the p53-dependent pathway and modification of Bax and XIAP proteins expression. The results have also provided important pharmacological backgrounds for the potential use of PP supercritical fluid extract as products for cancer prevention.
 ...
PMID:Supercritical carbon dioxide extract of Physalis peruviana induced cell cycle arrest and apoptosis in human lung cancer H661 cells. 1942 86

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.
 ...
PMID:Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. 1945 29

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. The expressions of DR4 and DR5, Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, are regulated by p53. In this study, the combined effects of nutlin-3 and TRAIL on apoptosis were investigated in HOS and HCT116 cells, which express wild-type p53. Nutlin-3 and TRAIL synergistically enhanced apoptosis owing to their intrinsic and extrinsic pathway signals, respectively. The increase in the Bid expression level and the decrease in the expression levels of anti-apoptotic proteins, c-FLIP and XIAP, were involved in this apoptosis enhancement. Furthermore, nutlin-3 activated the DR5 promoter and increased the expression levels of DR5 at mRNA and protein levels. These results indicate that the combination, treated with nutlin-3 and TRAIL, is useful for apoptosis induction in malignant cells expressing wild-type p53.
 ...
PMID:Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells. 1957 58

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.
 ...
PMID:Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. 1957 56

The inhibitors of apoptosis proteins (IAPs) act by directly blocking cleaved caspase-3 (XIAP) or the protein SMAC/DIABLO, an antagonist. The inhibition of XIAP activity or the increase of SMAC activity might improve the therapeutic response of the patients. This work evaluated the immunoexpression of IAPs and SMAC in colorectal carcinoma and their correlation with apoptotic index (AI), cellular proliferation, p53 protein immunoexpression and patient survival rate. TMA paraffin blocks were made with colorectal cancer tissue and adjacent non-tumorous mucosa of 130 patients, not submitted to radio or chemotherapy. Sections of 4 microm were processed by immunohistochemistry for survivin, XIAP, cIAP-1, cIAP-2 and SMAC, and the immunoexpression scores were obtained. They were correlated between each other and with the AI obtained by anti-cleaved caspase-3 and M30 (cleaved cytokeratin-18) antibodies, the cellular proliferation index, p53 protein immunoexpression and patient survival data. Direct correlation occurred between the four IAPs studied in tumor and non-tumorous mucosa tissues. SMAC, survivin, cIAP-1 and cIAP-2 were positively correlated with tumoral tissue AI. Cellular proliferation and p53 immunoexpression was positively correlated with XIAP, SMAC and cIAP-1 scores. Low cIAP-1 immunoexpression showed a tendency for correlation with shorter patient survival. Equilibrium between the activities of IAPs and SMAC was demonstrated by the direct correlation between their immunoexpression. Correlation between SMAC and AI confirmed the pro-apoptotic activity of this protein. XIAP showed no inverse correlation with AI. XIAP, SMAC and cIAP-1 play a role in colorectal tumorigenesis, as demonstrated by their direct correlation with cellular proliferation and p53 protein. The tendency for correlation between low cIAP-1 immunoexpression and survival might indicate a role for this protein as a prognostic marker in colorectal cancer.
 ...
PMID:Immunoexpression of inhibitors of apoptosis proteins and their antagonist SMAC/DIABLO in colorectal carcinoma: correlation with apoptotic index, cellular proliferation and prognosis. 1957 69

Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.
 ...
PMID:Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? 1959 Sep 64

Hepatocellular carcinoma (HCC) frequently includes abnormalities in cell cycle regulators, including up-regulated cyclin-dependent kinase (Cdks) activities due to loss or low expression of Cdk inhibitors. In this study, we show that xylocydine, a cyclin-dependent kinase (Cdk) specific inhibitor, is a good anti-cancer drug candidate for HCC treatment. Xylocydine (50muM) selectively down-regulates the activity of Cdk1 and Cdk2, accompanied by significant cell growth inhibition in HCC cells. Xylocydine also strongly inhibits the activity of Cdk7 and Cdk9, in vitro as well as in cell cultures, that is temporally associated with apoptotic cell death in xylocydine-induced HCC cells. This is associated with inhibition of phosphorylation of RNA polymerase II at serine residues 5 and 2, which are targets of Cdk7 and Cdk9, respectively. The effects on apoptosis are concomitant with changes in the levels of anti-apoptotic proteins, Bcl-2, XIAP, and survivin, which are markedly down-regulated, and pro-apoptotic molecules, p53 and Bax, which are elevated in HCC cells after treatment with xylocydine. The up-regulated level of p53 was associated with increased stability of the protein, as levels of Ser15 and Ser392 phsophorylated p53 are similarly elevated in the inhibitor treated cells. We demonstrated that xylocydine can effectively suppress the growth of HCC xenografts in Balb/C-nude mice by preferentially inducing apoptosis in the xenografts, whereas the drug did not cause any apparent toxic effect on other tissues. Taken together, these data suggest that the novel Cdk inhibitor xylocydine is a good candidate for an anti-cancer drug for HCC therapy.
 ...
PMID:Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. 1961 71

Busulfan (Bu) is a DNA-alkylating drug used in myeloablative pretransplant conditioning therapy for patients with myeloid leukemia (ML). A major obstacle to successful treatment is cellular Bu-resistance. To investigate the possible contribution of DNA hypermethylation to Bu-resistance, we examined the cytotoxic activity of combined 5-aza-2'-deoxycytidine (DAC) and Bu. Exposure of Bu-resistant B5/Bu250(6) ML cells to 0.5 microM DAC resulted in G2-arrest and apoptosis. The observed G2-arrest was associated with hypomethylation and subsequent expression of epigenetically controlled genes including p16(INK4A), activation of the p53 pathway, and phosphorylation of CDC2. The DAC-mediated apoptosis was partly due to hypomethylation and up-regulation of XAF1, which resulted in down-regulation of the anti-apoptotic proteins XIAP, cIAP1 and cIAP2. The pro-apoptotic PUMA and BNIP3 proteins were up-regulated while pro-survival STAT3 and c-MYC were suppressed. Combination of 0.05 microM DAC and 5 microg/ml Bu resulted in synergistic cytotoxicity, which was associated with PARP1 cleavage and activation of caspases 3 and 8, suggesting induction of an apoptotic response. P53 inhibition in B5/Bu250(6) cells using pifithrin-alpha alleviated these effects, suggesting a role for p53 therein; this observation was supported by the relative resistance of p53-null K562 cells to [DAC+Bu] combinations and by the effects of an anti-p53 shRNA on the OCI-AML3 cell line. We conclude that the synergistic effects of [DAC+Bu] are p53-dependent and involve cell cycle arrest, apoptosis induction and down-regulation of pro-survival genes. Our results suggest that, depending on tumor p53 status, incorporation of DAC might synergistically improve the cytoreductive efficacy of Bu-based pretransplant regimen in patients with ML.
 ...
PMID:5-Aza-2'-deoxycytidine sensitizes busulfan-resistant myeloid leukemia cells by regulating expression of genes involved in cell cycle checkpoint and apoptosis. 1973 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>