Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The histone deacetylase (HDAC) inhibitor, apicidin, has been shown to suppress the growth of human breast cancer cells. In this article, we examined the ability of apicidin to inhibit the proliferation of human breast cancer cell lines. Cell cycle regulators and apoptotic cell death were determined using Western blot analysis and DAPI fluorescence staining, respectively. Apicidin treatment produced significant increases in acetylated H3 and H4 levels. In MCF-7 cells, the expression of ERalpha and ERbeta was decreased in a dose-dependent manner after apicidin treatment. However, ERbeta expression was not changed in MDA-MB-231 cells. Apicidin (300 nM) significantly induced expression of p21Waf1 and p27Kip1. Expression levels of cell cycle regulator proteins (cyclin D1/CDK 4 and cyclin E/CDK 2) were markedly decreased by apicidin in MCF-7 cells, but not in MDA-MB-231 cells. Cell cycle analysis indicated that apicidin increased the proportion of cells in the G1 phase and decreased the proportion of cells in the S phase in MCF-7 cells. Significantly, increase in sub-G1 populations was observed in MCF-7 cells by apicidin treatment. Apicidin treatment resulted in the induction of apoptotic cell death which was confirmed by DAPI staining. Additionally, apicidin significantly increased the bax/bcl-2 ratio in MCF-7 cells. These results suggest that apicidin inhibits proliferation of ER-positive MCF-7 breast cancer cells by altering the expression of cell cycle regulator proteins and inducing apoptotic cell death. These distinctive cell-specific effects of apicidin on the modulation of cell cycle arrest and apoptosis may be associated with ERalpha-mediated transcriptional regulation.
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PMID:Modulation of cell cycles and apoptosis by apicidin in estrogen receptor (ER)-positive and-negative human breast cancer cells. 1831 54

The anticancer effects of kotomolide A (KTA), a new butanolide constituent isolated from the leaves of Cinnamomum kotoense (Lauraceae), on the two human breast cancer cell lines MCF-7 and MDA-MB-231, were first investigated in our study. KTA exhibited selectively antiproliferative effects in cancer cell lines without showing any toxicity in normal mammary epithelial cells. Treatment of cancer cells with KTA to trigger G2/M phase arrest was associated with increased p21/WAF1 levels and reduced amounts of cyclin A, cyclin B1, cdc2 and cdc25C. KTA induced cancer cell death treatment by triggering mitochondrial and death receptor 5 (DR5) apoptotic pathways, but did not act on the Fas receptor. Exposure of MCF-7 and MDA-MB-231 cells to KTA resulted in cellular glutathione reduction and ROS generation, accompanied by JNK activation and apoptosis. Both antioxidants, NAC and catalase, significantly decreased apoptosis by inhibiting the phosphorylation of JNK and subsequently triggering DR5 cell death pathways. The reduction of JNK expression by siRNA decreased KTA-mediated Bim cleavage, DR5 upregulation and apoptosis. Furthermore, daily KTA i.p. injections in nude mice with MDA-MB-231 s.c. tumors resulted in a 50% decrease of mean tumor volume, compared with vehicle-treated controls. Taken together, the data show that cell death of breast cancer cells in response to KTA is dependent upon ROS generation and JNK activation, triggering intrinsic and extrinsic apoptotic pathways. The ROS/JNK pathway could be a useful target for novel approaches in breast cancer chemotherapy.
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PMID:Involvement of reactive oxygen species/c-Jun NH(2)-terminal kinase pathway in kotomolide A induces apoptosis in human breast cancer cells. 1837 81

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands inhibit cell proliferation and induce apoptosis in cancer cells. Here we wished to determine whether the PPARgamma ligand induces apoptosis and cell cycle arrest of the MDA-MB-231 cell, an estrogen receptor alpha negative breast cancer cell line. The treatment of MDA-MB-231 cell with PPARgamma ligands was shown to induce inhibition of cell growth in a dose-dependent manner as determined by MTT assay. Cell cycle analysis showed a G1 arrest in MDA-MB-231 cells exposed to troglitazone. An apoptotic effect by troglitazone demonstrated that apoptotic cells elevated by 2.5-fold from the control level at 10 microM, to 3.1-fold at 50 microM and to 3.5-fold at 75 microM. Moreover, troglitazone treatment, applied in a dose-dependent manner, caused a marked decrease in pRb, cyclin D1, cyclin D2, cyclin D3, Cdk2, Cdk4 and Cdk6 expression as well as a significant increase in p21 and p27 expression. These results indicate that troglitazone causes growth inhibition, G1 arrest and apoptotic death of MDA-MB-231 cells.
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PMID:Induction of G1 phase arrest and apoptosis in MDA-MB-231 breast cancer cells by troglitazone, a synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligand. 1847 41

We examined the mechanisms by which daidzein inhibits the growth of breast cancer cells. First, we investigated its antiproliferative effects in MCF-7 and MDA-MB-453 cells exposed to 1-100 microM daidzein for 24, 48, or 72 h. Daidzein significantly inhibited cell proliferation in a dose- and time-dependent manner (p<0.05) and resulted in significant cell cycle arrest in the G1 and G2/M phases after 72 h of treatment at concentrations over 5 and 10 microM in MCF-7 and MDA-MB-453 cells, respectively (p<0.05). In addition, daidzein caused the accumulation of cells in sub-G0 phase in a dose-dependent manner in MDA-MB-453 (p<0.05), but not MCF-7, cells. As another biomarker of apoptosis induction, caspase-9 activity was significantly increased by daidzein in both cells. To investigate the effects of daidzein on the proteins regulating cell cycle arrest, cells were treated with 100 microM daidzein for 72 h. Similar changes in the expression of regulatory proteins were detected in both cells. Daidzein treatment resulted in decreases in cyclin D, CDK2, and CDK4, whereas the expression of CDK6 and cyclin E was unchanged. The protein expression of CDK1 related to the G2/M phase decreased markedly with daidzein treatment, whereas slight expression of cyclins A and B occurred. Daidzein treatment increased the expression of the CDK inhibitors p21(Cip1) and p57(Kip2), but not that of p27(Kip1). Thus, daidzein exerts its anticancer effects in human breast cancer cells via cell cycle arrest at the G1 and G2/M phases.
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PMID:Daidzein causes cell cycle arrest at the G1 and G2/M phases in human breast cancer MCF-7 and MDA-MB-453 cells. 1854 20

Antrodia camphorata (A. camphorata) has been shown to induce apoptosis in cultured human breast cancer cells (MDA-MB-231). In this study, we report the effectiveness of the fermented culture broth of A. camphorata in terms of tumor regression as determined using both in vitro cell culture and in vivo athymic nude mice models of breast cancer. We found that the A. camphorata treatment decreased the proliferation of MDA-MB-231 cells by arresting progression through the G1 phase of the cell cycle. This cell cycle blockade was associated with reductions in cyclin D1, cyclin E, CDK4, cyclin A, and proliferating cell nuclear antigen (PCNA), and increased CDK inhibitor p27/KIP and p21/WAF1 in a dose and time-dependent manner. Furthermore, the A. camphorata treatment was effective in delaying tumor incidence in the nude mice inoculated with MDA-MB-231 cells as well as reducing the tumor burden when compared to controls. A. camphorata treatment also inhibited proliferation (cyclin D1 and PCNA) and induced apoptosis (Bcl-2 and TUNEL) when the tumor tissue sections were examined histologically and immunohistochemically. These results suggest that the A. camphorata treatment induced cell cycle arrest and apoptosis of human breast cancer cells both in vitro and in vivo.
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PMID:Antrodia camphorata inhibits proliferation of human breast cancer cells in vitro and in vivo. 1855 Feb 46

Although the primary response to Adriamycin (doxorubicin) in p53 mutant MDA-MB231 and p53 null MCF-7/E6 breast tumor cells is apoptotic cell death, the residual surviving population appears to be in a state of senescence, based on cell morphology, beta galactosidase staining, induction of p21(waf1/cip1) and down regulation of cdc2/cdk1. Suppression of apoptosis in MDA-MB231 and MCF-7/E6 cells treated with Adriamycin using the broad spectrum caspase inhibitor, zvad-Fmk, results in substantial induction of autophagy. Overall sensitivity to Adriamycin, measured by clonogenic survival, is not altered in the cells undergoing autophagy, consistent with autophagy contributing to cell death in response to Adriamycin. The free radical scavengers, glutathione and N-acetyl cysteine attenuate the accelerated senescence response to Adriamycin in MCF-7 cells as well as in MDA-MB231 and MCF-7/E6 cells, but protect primarily the MCF-7 cells, indicating that reactive oxygen is unlikely to be directly responsible for Adriamycin toxicity in breast tumor cells. Expression of caspase 3 or induced expression of c-myc in MCF-7 cells fails to abrogate accelerated senescence induced by Adriamycin. Taken together, these studies suggest that accelerated senescence induced by Adriamycin is similar in cells with wild type p53 and in cells lacking functional p53 with regard to the upregulation of p21(waf1/cip1), down regulation of cdc2 and the involvement of reactive oxygen species. Furthermore, accelerated senescence, autophagy and apoptosis all appear to be effective in suppressing self-renewal capacity in breast tumor cells exposed to Adriamycin.
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PMID:Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin. 1918 64

Chemotherapy comprises part of successful treatment regimens for breast cancer, however, up to 50% of patients develop resistance. Stress in cancer patients can equate to poor chemotherapeutic responses. We hypothesize that drug resistance may be associated with stress hormone-induced alterations in breast cancer cells. To test this hypothesis, MDA-MB-231 cells were cultured with paclitaxel and/or cortisol, norepinephrine and epinephrine and cytotoxicity, cell cycle analyses, genomic and proteomic analyses were performed. Paclitaxel-mediated cytotoxicity and G2/M cell cycle arrest were reversed significantly by stress hormones. Genomic and proteomic analyses revealed that stress hormones modulated beta-tubulin isotypes and significantly altered genes and proteins involved in regulation of the G2/M transition, including cyclin-dependent kinase-1 (CDK-1). Inhibition of CDK-1 abrogated stress hormone-mediated reversal of paclitaxel-induced cytotoxicity, indicating that the protective effect of stress hormones act through a CDK-1-dependent mechanism. These data demonstrate that stress hormones interfere with paclitaxel efficacy and contribute significantly to drug resistance.
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PMID:Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway. 1956 Feb 78

Schizandrin is one of the main dibenzocyclooctadiene lignans present in the fruit of Schisandra chinensis (Schisandraceae). Biological activities including hepatoprotective, antiviral and neuroprotective effects of schizandrin and other dibenzocyclooctadiene lignans have been reported previously. However, the antiproliferative effect of schizandrin against human cancer cells has been poorly determined to date. This study examined the antiproliferative effect of schizandrin in human breast cancer cells. Schizandrin exhibited growth inhibitory activities in cultured human breast cancer cells, and the effect was the more profound in estrogen receptor (ER)-positive T47D cells than in ER-negative MDA-MB-231 cells. When treated with the compound in T47D cells, schizandrin induced the accumulation of a cell population in the G0/G1 phase, which was further demonstrated by the induction of CDK inhibitors p21 and p27 and the inhibition of the expression of cell cycle checkpoint proteins including cyclin D1, cyclin A, CDK2 and CDK4. These results suggest that schizandrin inhibits cell proliferation through the induction of cell cycle arrest with modulating cell cycle-related proteins in human breast cancer cells.
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PMID:Growth inhibition and cell cycle arrest in the G0/G1 by schizandrin, a dibenzocyclooctadiene lignan isolated from Schisandra chinensis, on T47D human breast cancer cells. 1958 70

Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits anti-carcinogenic effect. The results of present study showed that NFD inhibited the proliferation of breast cancer MDA-MB-231 cells through the induction of S-phase arrest and apoptosis. NFD-induced S-phase arrest was associated with a marked decrease in the protein expression of cyclin A, cyclin B, and cyclin-dependent kinase (Cdk)2. NFD-induced apoptosis was characterized by increase of sub-G1 population, phosphatidylserine (PS) externalization, and activation of caspases. Moreover, up-regulation of Bad and down-regulation of Bcl-2, Bcl-X(L), and survivin led to the loss of mitochondrial membrane potential (DeltaPsim), the release of cytochrome c and sequential activation of caspase-9 and caspase-3. NFD activated c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK) in MDA-MB-231 cells. Inhibitors of JNK (SP600125) and ERK (PD98059), but not p38 MAPK (SB203580) suppressed NFD-induced S-phase arrest and apoptosis in MDA-MB-231 cells. Both SP600125 and PD98059 attenuated Bad up-regulation, and reversed down-regulation of Bcl-2, Bcl-X(L), survivin, cyclin A, cyclin B, and Cdk2 in NFD-treated cells. Taken together, our data show that JNK and ERK-signaling pathways play important roles in NFD-mediated S-phase arrest and apoptosis of MDA-MB-231 cells.
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PMID:Naphtho[1,2-b]furan-4,5-dione induces apoptosis and S-phase arrest of MDA-MB-231 cells through JNK and ERK signaling activation. 1974 39

Patients with advanced breast cancer frequently develop bone metastases, and at this stage, the disease is considered incurable. Here, we show that a 6-week course of weekly administration of doxorubicin (2 mg/kg), followed 24 hours later by the bisphosphonate zoledronic acid (100microg/kg), causes substantial inhibition of MDA-MB-436 breast tumor burden in bone of immunocompromised mice, compared with administration of the single agents. Molecular analysis of tumors from animals treated sequentially with doxorubicin followed by zoledronic acid showed reduced numbers of proliferating tumor cells and decreased expression of cyclins E1, B, D1, and D3 as well as cdk2 and cdk4. Tumors from the sequential treatment group also displayed increased levels of apoptosis, increased expression of bcl2-associated X protein, decreased expression of B-cell chronic lymphocytic leukemia/lymphoma 2, and activation of caspase 3, 8, and 9. Zoledronic acid caused a small reduction in tumor volume, reduced tumor cell proliferation, and decreased expression of cyclins D1 and D3, compared with tumors from animals treated with saline or doxorubicin. Doxorubicin had no effect on tumor growth, cell cycle, or apoptosis in vivo, but did cause increased accumulation of a bisphosphonate in MDA-MB-436 cells in vitro, suggesting that doxorubicin may affect subsequent uptake of zoledronic acid. In support of this, accumulation of unprenylated Rap1A, a surrogate marker of zoledronic acid, was only detected in tumors following sequential treatment, and not following treatment with zoledronic acid alone. Our data are the first to show the specific molecular pathways by which sequential treatment with doxorubicin and zoledronic acid induce tumor cell apoptosis and inhibit proliferation in an in vivo model of breast tumor growth in bone.
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PMID:Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone. 1978 17


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