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)

Dietary flavonols have been found to possess preventive and therapeutic potential against several kinds of cancers. This study is conducted to investigate the anti-proliferation effects of kaempferol, a major component of food flavonols, against colon cancer cells. In the human HCT116 colon cancer cell line, kaempferol induced p53-dependent growth inhibition and apoptosis. Furthermore, kaempferol was found to induce cytochrome c release from mitochondria and activate caspase-3 cleavage. The Bcl-2 family proteins including PUMA were involved in this process. Kaempferol also induced ATM and H2AX phosphorylation in HCT116 cells, inhibition of ATM by a chemical inhibitor resulted in abrogation of the downstream apoptotic cascades. These findings suggest kaempferol could be a potent candidate for colorectal cancer management.
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PMID:Kaempferol induces apoptosis in human HCT116 colon cancer cells via the Ataxia-Telangiectasia Mutated-p53 pathway with the involvement of p53 Upregulated Modulator of Apoptosis. 1902 73

This study is the first to investigate the anticancer effect of isoliquiritigenin (ISL) in human cervical carcinoma HeLa cells. The results reveal that ISL inhibits HeLa cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Blockade of cell cycle is associated with increased activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by ISL phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, ISL-mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2, and cdc25C, and increases in the phosphorylation of Chk2, cdc25C, and cdc2. The specific ATM inhibitor caffeine significantly decreased ISL-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. ISL induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl-2 and Bcl-X(L), and subsequently triggering mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase-9 inhibitor blocked ISL-induced apoptosis, indicating that caspase-9 activation is involved in ISL-mediated HeLa cell apoptosis. These findings suggest that ISL may be a promising chemopreventive agent against human uterine cervical cancer.
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PMID:Shallot and licorice constituent isoliquiritigenin arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and initiation of the mitochondrial system in human cervical carcinoma HeLa cells. 1953 69

Doxorubicin is known to have cumulative dose-dependent cardiotoxicity, and a tumor suppressor protein p53 has been implicated in the pathogenesis of doxorubicin cardiotoxicity. However, how p53 is induced by doxorubicin and mediates the cardiotoxic effects of doxorubicin remains elusive. In cultured cardiac myocytes, doxorubicin induced oxidative stress, DNA damage, ATM activation, and p53 induction. A free radical scavenger NAC attenuated all of these events, whereas an ATM kinase inhibitor wortmannin attenuated doxorubicin-induced ATM activation and p53 induction but not oxidative stress. Doxorubicin treatment in vivo also induced oxidative stress, DNA damage, ATM activation, and p53 accumulation. These observations suggest that p53 induction by doxorubicin is mediated by oxidative DNA damage-ATM pathway. Doxorubicin-induced contractile dysfunction and myocyte apoptosis in vivo were attenuated in heterozygous p53 deficient mice and cardiac-restricted Bcl-2 transgenic mice, suggesting that myocyte apoptosis plays a central role downstream of p53 in doxorubicin cardiotoxicity. We also tested whether pitavastatin exerts protective effects on doxorubicin cardiotoxicity. Pitavastatin attenuated doxorubicin-induced oxidative stress, DNA damage, ATM activation, p53 accumulation, and apoptosis in vitro. Pitavastatin also attenuated myocyte apoptosis and contractile dysfunction in vivo. The beneficial effects of pitavastatin were reversed by intermediate products of the mevalonate pathway that are required for the activation of Rac1, and Rac1 inhibitor exhibited cardioprotective effects comparable to those of pitavastatin. These data collectively suggest that doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition.
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PMID:Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity. 1966 Apr 69

This study is the first to investigate the anticancer effect of tricetin in human breast adenocarcinoma MCF-7 cells. Results reveal that tricetin inhibits MCF-7 cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Cell cycle blockade is associated with increased activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by tricetin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, tricetin-mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2 and cdc25C, and increases in the phosphorylation of Chk2, cdc25C and cdc2. The specific ATM inhibitor caffeine significantly decreased tricetin-mediated G2/M arrest by inhibiting the phosphorylation of p53 (serine 15) and Chk2. Tricetin-induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl-2 and Bcl-X(L), and subsequently triggering the mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase-9 inhibitor blocked tricetin-induced apoptosis, indicating that caspase-9 activation is involved in tricetin-mediated MCF-7 cell apoptosis. These findings suggest that tricetin may be a promising chemopreventive agent against human breast cancer.
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PMID:Tricetin, a dietary flavonoid, inhibits proliferation of human breast adenocarcinoma mcf-7 cells by blocking cell cycle progression and inducing apoptosis. 1970 44

Beta-carotene acts as an antioxidant or a pro-oxidant depending on the concentrations that cells are treated with. Oxidative DNA damage is related to apoptosis of various cells. Ataxia-telangiectasia-mutated (ATM), a sensor for DNA-damaging agents, activates a variety of effectors in multiple signaling pathways, such as DNA repair and apoptosis. In the present study, we investigated whether a high concentration of beta-carotene induces apoptosis of gastric adenocarcinoma (AGS) cells and whether ATM is involved in beta-carotene-induced apoptosis of AGS cells. We found that beta-carotene (100 micromol/L) induced apoptosis (determined by cell viability), DNA fragmentation, and the protein levels of p53 and Bcl-2 in AGS cells. ATM levels in the nucleus decreased from beta-carotene in AGS cells. beta-Carotene-induced alterations, including an increase in DNA fragmentation and p53 levels and a decrease in nuclear ATM and cellular Bcl-2 levels, were inhibited in the cells transfected with full-length ATM cDNA compared to wild-type cells or the cells transfected with control vector plasmid control DNA vector (pcDNA). In conclusion, beta-carotene induces apoptosis by increasing apoptotic protein p53 and decreasing anti-apoptotic Bcl-2 as well as nuclear ATM in AGS cells. Nuclear loss of ATM may be the underlying mechanism of beta-carotene-induced apoptosis of gastric cancer cells.
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PMID:Mechanism of beta-carotene-induced apoptosis of gastric cancer cells: involvement of ataxia-telangiectasia-mutated. 1972 50

Genistein is a major isoflavonoid in dietary soybean, commonly consumed in Asia. Genistein exerts inhibitory effects on the proliferation of various cancer cells and plays an important role in cancer prevention. However, the molecular and cellular mechanisms of genistein on human ovarian cancer cells are still little known. We show that exposure of human ovarian cancer HO-8910 cells to genistein induces DNA damage, and triggers G2/M phase arrest and apoptosis. Furthermore, we also found that checkpoint proteins ATM and ATR are phosphorylated and activated in the cells treated with genistein. It is also shown that genistein increases the phosphorylation and activation of Chk1 and Chk2, which results in the phosphorylation and inactivation of phosphatases Cdc25C and Cdc25A, and thereby the phosphorylation and inactivation of Cdc2 which arrests cells in G2/M phase. Moreover, genistein enhances the phosphorylation and activation of p53, while decreases the ratio of Bcl-2/Bax and Bcl-xL/Bax and the level of phosphorylated Akt, which result in cells undergoing apoptosis. These results demonstrate that genistein-activated ATM-Chk2-Cdc25 and ATR-Chk1-Cdc25 DNA damage checkpoint pathways can arrest ovarian cancer cells in G2/M phase, and induce apoptosis while the cellular DNA damage is too serious to be repaired. Thus, the antiproliferative, DNA damage-inducing and pro-apoptotic activities of genistein are probably responsible for its genotoxic effects on human ovarian cancer HO-8910 cells.
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PMID:Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. 1973 43

The purpose of the present study is to evaluate the effects of arsenic trioxide (ATO) on human acute promyelocytic leukemia NB-4 cells. Microculture tetrazolium test, bromodeoxyuridine (BrdU) cell proliferation assay, caspase 3 activity assay, cell-based nuclear factor kappa B (NF-kappaB) phosphorylation measurement by ELISA and real-time RT-PCR were employed to appraise the effects of ATO on metabolic activity, DNA synthesis, induction of programmed cell death and NF-kappaB activation. The suppressive effects of ATO on metabolic potential, cell proliferation and NF-kappaB activation were associated with induction of apoptosis in NB-4 cells. In addition, an expressive enhancement in mRNA levels of p73, cyclin-dependent kinase inhibitor 1A (p21), tumor protein 53-induced nuclear protein 1 (TP53INP1), WNK lysine deficient protein kinase 2 (WNK2) and lipocalin 2 coupled with a significant reduction in transcriptional levels of NF-kappaB inhibitor beta (IKK2), Nemo, BCL2-like 1 (BCL-X(L)), inhibitor of apoptosis protein 1 (cIAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin, Bcl-2, TIP60, ataxia telangiectasia (ATM), SHP-2 and sirtuin (SIRT1) were observed. Altogether, these issues show for the first time that ATO treatment could trammel cell growth and proliferation as well as induces apoptosis in NB-4 cells through induction of transcriptional levels of p73, TP53INP1, WNK2, lipocalin 2 as well as suppression of NF-kappaB-mediated induction of BCL-X(L), cIAP2, XIAP and survivin. Furthermore, the inductionary effects of ATO on transcriptional stimulation of p73 might be through cramping the NF-kappaB module (through suppression of p65 phosphorylation as well as transcriptional hindering of IKK2, ATM and Nemo) along with diminishing the mRNA expression of TIP60, SHP-2 and SIRT1.
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PMID:Arsenic trioxide induces apoptosis in NB-4, an acute promyelocytic leukemia cell line, through up-regulation of p73 via suppression of nuclear factor kappa B-mediated inhibition of p73 transcription and prevention of NF-kappaB-mediated induction of XIAP, cIAP2, BCL-XL and survivin. 1976 17

Hepatocellular carcinoma is chemoresistant to many anticancer drugs. Tunicamycin, an N-glycosylation inhibitor, causes unfolded protein response and is widely used as pharmacological inducer of endoplasmic reticulum stress. In this study, several designs were used to investigate the resistance mechanism to camptothecin and etoposide in hepatocellular carcinoma Hep3B cells. Tunicamycin significantly inhibited apoptosis induced by camptothecin or etoposide. Tunicamycin neither modified the topoisomerase levels nor inhibited the ATM activation caused by camptothecin and etoposide. The data suggest that tunicamycin-induced resistance may result from the downstream events of drug-trapped topoisomerase-DNA complexes and DNA double-strand breaks. Camptothecin and etoposide caused an increase of protein expression of several cell-cycle regulators and induced the cleavage of Bcl-2 family of proteins. These intracellular molecular events were abolished by tunicamycin. A design of postaddition of tunicamycin demonstrated that G1 checkpoint arrest contributed to the resistance mechanism. Curcumin, another G1 arrest-inducing agent in this study, was able to induce a similar resistant effect. Furthermore, the cells transfected with GRP78 siRNA were partly resistant to tunicamycin-induced apoptosis but not the inhibitory effect on cell-cycle regulators indicating that GRP78 and G1 arrest are two independent factors to tunicamycin-induced resistance mechanism. In conclusion, the data suggest that tunicamycin induces the resistance to topoisomerase inhibitors through GRP78 up-regulation and G1 arrest of the cell cycle. The findings also prompt the deliberation that the resistance can be caused during combined administration of chemotherapeutic drugs and Chinese herbal medicines, which induce endoplasmic reticulum stress and/or cell-cycle arrest in cancer cells.
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PMID:Tunicamycin induces resistance to camptothecin and etoposide in human hepatocellular carcinoma cells: role of cell-cycle arrest and GRP78. 1977 12

In this study, we investigated the protective effect of losartan as an AT1 receptor antagonist by evaluating the expression of apoptosis-regulatory genes that contribute to the progressive damage in the renal tubules of hyperoxaluric rats. Rats were divided into 4 groups of 10 each; control (C), ethylene glycol (EG), ethylene glycol + losartan (EG + L) and Losartan (L). For 4 weeks 0.8% EG, as a precursor for oxalate, was administered to EG and EG + L and losartan (300 mg/l) was administered to groups EG + L and L. Urine and blood samples were collected for biochemical determination. Bcl-2, bax, caspase-3 and TGF-beta 1 antibodies were used for immunohistochemistry. Apoptosis was determined by TUNEL method. A marked increase in urinary oxalate levels of the rats in EG and EG + L groups was found. In the EG group a diffuse amount of oxalate crystals into the tubular lumina and interstitium in the cortex was observed. In the EG group GBM thickening, interstitial fibrosis and tubular atrophy with infiltration of mononuclear cell findings reduced in the EG + L group were presented as well. In the EG group, immunoreactivity of TGF-beta 1 was increased in glomeruli and tubuli. In the EG + L group, immunoreactivity of TGF-beta 1 was decreased compared to the EG group. Bax expression increased in the renal tubules of EG group and reduced in the EG + L group comparing to the control. In the EG + L group, the immunoreactivity of bcl-2 was increased in glomeruli. In EG + L treated group, number of caspase-3 immunopositive cells were decreased compared to all groups (P < 0.01). Apoptotic cells were increased in the EG-treated group compared to the other groups. Decreased apoptotic cell number was observed in the EG + L compared to the EG group (P < 0.01). Our findings suggest that losartan may provide a beneficial effect against tubulointerstitial damage and decrease renal tubular apoptosis caused by hyperoxaluria.
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PMID:Antiapoptotic effect of angiotensin-II type-1 receptor blockade in renal tubular cells of hyperoxaluric rats. 2015 Nov 16

The aim of the current study was to determine the signaling differences between gamma- and proton beam-irradiations. A549 lung adenocarcinoma cells were irradiated with 2 Gy proton beam or gamma-radiation. Proton beam was found to be more cytotoxic than gamma-radiation. Proton beam-irradiated cells showed phosphorylation of H2AX, ATM, Chk2, and p53. The mechanism of excessive cell killing in proton beam-irradiated cells was found to be upregulation of Bax and downregulation of Bcl-2. The noteworthy finding of this study is the biphasic activation of the sensor proteins, ATM, and DNA-PK and no activation of ATR by proton irradiation.
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PMID:Low energy proton beam induces efficient cell killing in A549 lung adenocarcinoma cells. 2021 May 20


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