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)

Obesity is a risk factor for postmenopausal breast cancer and is associated with poor prognosis. Leptin, a cytokine synthesized in adipose tissue, has been implicated as a link between obesity and breast cancer. In the present study, the effects of leptin on cell proliferation and proteins associated with leptin signaling and/or breast cell growth were investigated in ER-positive, MCF-7, T47-D and MDA-MB-361, and ER-negative, MDA-MB-231 and SK-BR-3, breast cancer cell lines. MDA-MB-361 and SK-BR-3 also overexpress HER2/neu. For proliferation assays, 96-well plates were used and for protein determinations cells were synchronized in 6-well plates for 18-24 h in serum-free medium. Leptin was added at 0, 5, 10, 25, 50 and 100 ng/ml for 24 and 48 h. For Western blot analyses, protein extracts were probed for Ob-Rb, Ob-R, leptin, Jak2, PI3K, Stat3, p-Stat3, PCNA, cyclin D1, Cox-2, VEGF, Bcl-2, Bcl-xL, Bax, insulin, IGF-I, IGFBP3, IGF-IRalpha, aromatase, CYP1A1 and CYP1B1. Overall, except for MCF-7 cells, leptin stimulated proliferation in all lines. MCF-7 cells expressed higher levels of Ob-Rb, Jak2, PI3K, Stat3 and p-Stat3 in a dose-dependent manner to 50 ng/ml at 24 h; and IGF-IRalpha increased at 24 h. Cyclin D1 and Cox-2 levels increased with leptin treatment. Higher CYP1B1 expression was observed at both 24 and 48 h. In MDA-MB-231 cells, p-Stat3 and Bcl-xL were increased at 48 h; whereas PCNA and cyclin D1 expression increased in leptin-treated cells at 24 and 48 h. In T47-D cells, Jak2 and Stat3 were elevated at higher leptin concentrations at 24 and 48 h. However, p-Stat3 and PCNA demonstrated an increase only in 48-h leptin-treated cells. Furthermore, cyclin D1 exhibited higher expression at both 24 and 48 h, while Bcl-xL expression was lower with increasing concentrations of leptin at 48 h. In MDA-MB-361 cells, Ob-Rb and VEGF increased at 24 and 48 h; whereas PI3K, Stat3, PCNA and insulin levels increased in leptin-treated MDA-MB-361 cells after 48 h. Bcl-2 and IGF-IRalpha were decreased at 24 h and a dose-dependent increase at 48 h was noted. Higher expression of CYP1B1 was observed with leptin for 24 h. In SK-BR-3 cells, Ob-R increased at both 24 and 48 h. A similar trend was found for IGF-I and IGFBP3 expression. Higher levels of Jak2 and PI3K were observed after 24 h. Interestingly, there was a gradual increase of leptin expression at 24 h, but a gradual decrease at 48 h in relation to the dose of leptin. In contrast, PCNA and IGF-IRalpha showed a decline at 24 h and an increase at 48 h. Elevated levels of cyclin D1, VEGF and Bax were detected at 48 h in cells and increased Cox-2 expression was observed at 24 h. These data indicate that leptin may influence breast cancer development in relation to ER status as well as to the presence or absence of HER2. Continued study on leptin may be helpful for a better understanding of breast cancer development in obese women.
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PMID:Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. 1748 72

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies.
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PMID:Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1. 1757 37

The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are expanding the clinical knowledge that is already documented in traditional texts. The herbs that are traditionally used for anti-cancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclo-oxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies or reducing toxicity. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials may be preferable, smaller studies with appropriate endpoints and surrogate markers for anti-angiogenic response could help to prioritize agents for larger, resource-intensive phase iii trials.
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PMID:Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 2. 1757 49

Metastases in renal carcinoma are diagnosed at initial diagnosis in 25% examinees. Traditional renal carcinoma has higher metastatic potential, is associated with worse survival of the patients compared to papillary cancer. We studied cytological characteristics of renal carcinoma metastases to the pleura in comparison with histological studies of the primary lesion using immunohistochemical findings. We examined cytologically pleural liquid in renal carcinoma metastases to the pleura in 6 patients (2.3% of carcinomatous pleuricies). High efficacy was shown by a cytocentrifuge CYTOSPIN-4. In 3 cases initial cancer was renal cell carcinoma, pleural exudation developed 2 years later, clear cell carcinoma appeared 6 years later and papillary cancer--10 years later. In the other 3 cases malignant cells were detected in new-onset cases. Renal carcinoma was diagnosed in one case. Cytological preparations were studied with identification of cytological signs typical for classic clear cell, granulocell and papillary renal cancer. Immunohistochemical examination of primary tumor lesion in the kidney discovered high proliferative activity of tumor cells by Ki-67 index to 5.28%. The tumors had solitary Bcl-2 positive cells. Expression of mutant p-53 took place in 0.93%. Her-2/neu hyperexpression was not found in the tumors of the above patients. Such immunohistochemical parameters point to poor prognosis. This is confirmed by renal carcinoma metastases to the pleura.
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PMID:[Pleural metastases of renal carcinoma]. 1757 98

The aim of our work was to study the expression of apoptotic signaling proteins and its relation to apoptosis level in neuroendocrine system of HER2/neu transgenic mice in aging. SHR mice served as controls. Bcl-2, Mcl-1, p53 and caspase-8 were demonstrated by immunohistochemistry in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and relative content of apoptotic neurosecretory cells was determined. It was demonstrated that apoptosis regulation in different nuclei in old SHR mice was mediated by various signaling pathways: in SON, p53-independent cascade was activated, while in PVN it was p53-dependent. Overexpression of HER2/neu was shown to protect against the age-related apoptosis activation in neurosecretory centers. HER2/neu suppressed the synthesis of proapoptotic protein p53, causing the reduction of caspase-8 expression, that resulted in the increased survival of neurosecretory cells in aging.
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PMID:[Age-dependent peculiarities of apoptotic marker proteins expression in the neuroendocrine system of Her2/neu transgenic mice]. 1772 67

We report a new series of Herceptin-platinum(II) binding complexes, Her-nLPt(II) (Her denotes Herceptin; L denotes diamino ligands and L=L1-L4; n=1, 5, or 10). Solution chemistry studies have shown that these complexes are stable under physiological conditions (pH 7.4 in PBS). The platinum(II) compound L1Pt(II)Cl(2) inhibits the growth of a panel of human cancer cell lines at sub-micromolar concentrations. Remarkable cancer-cell-specific cytotoxicity was observed with Her-nL1Pt(II) (n=1, 5, 10) toward Her2/neu-overexpressing cancer cells (SK-BR-3 and SK-OV-3) over normal fibroblast cells. Annexin V apoptosis assays in SK-BR-3 and low-Her2/neu-expressing MCF-7 breast cancer cells further confirmed the critical role of Herceptin with this cancer-cell-specific agent. It was also found that the L1Pt(II)Cl(2) complex is an efficient regulator of the apoptotic genes Bcl-2 in the treated SK-BR-3 cells. Also, enhanced regulatory effects were observed in Her-10L1Pt(II). Taken together, this study suggests a new approach for the development of mAb-platinum(II)-based targeting agents for the treatment of human cancers.
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PMID:Herceptin-platinum(II) binding complexes: novel cancer-cell-specific agents. 1836 39

Tyrosine kinase receptor HER2/neu plays an important role in a number of processes including carcinogenesis. The oncogenic characteristics of HER2/neu are associated with its ability to affect a variety of apoptotic pathways creating, this way, an antiapoptotic environment in the cells overexpressing this protein. The aim of our work was to investigate the features of apoptosis regulation in hypothalamic neurosecretory cells of HER2/neu transgenic mice in aging. We detected the apoptosis protein expression (Bax, c-Raf) in comparison with apoptosis level and functional activity (vasopressin concentration) in neuroendocrine system. Besides, we studied the level of 17beta-estradiol in blood plasma. 17beta-estradiol is one of possible antiapoptotic factors in neurons. We show that the apoptosis of neuroendocrine cells increases in aged wild type mice, but not in HER2/neu ones. Recently we obtained that the mechanism of apoptosis suppression in transgenic mice is the block of p53-dependent apoptosis cascade, and it is the cause of caspadse-8 decrease and dysregulation of Bcl-2 and Mcl-1 antiapoptotic protein synthesis. In this study it has been shown that Bax concentration decreases and c-Raf-1 expression does not change. 17beta-estradiol does not decrease in plasma of aged transgenic mice and it is the factor, which can play a positive role in neuroendocrine cells survival. Besides, the vasopressin synthesis increases in young and old HER2 mice. These facts result in the increased survival of neurosecretory cells in old transgenic mice.
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PMID:[Apoptosis regulation in hypothalamic neurosecretory cells of HER2/neu transgenic mice in ontogenesis]. 1838 7

Incidental prostate cancer (PCa) has been demonstrated at autopsy in about 80% of men aged 80 years and above and also in 10%-15% of younger men aged 30-50 years in the United States. These data imply a wide variation in aggressiveness of prostate cancer, from indolent tumors to aggressive cancers that kill the patients. The use of prostate specific antigen (PSA) in screening for PCa may detect even indolent disease for which radical prostatectomy may not be necessary. Currently available criteria such as histological grade, PSA level, stage of the disease do not always predict outcome. Furthermore, only about 80% of men with metastatic PCa will respond to first line hormone manipulation and once the patient develops hormone resistant prostate cancer (HRPCa), survival remains poor. Recent genomic and proteomic studies have provided many novel molecular markers that may help to redefine prognostic parameters. This paper is a review of studies using these novel markers in order to determine whether prostate cancer patients with the following characteristics have more aggressive cancer than those without: a) high serum levels of cathepsin B, survivin, Her - 2 / neu, IGFBP-2; b) low serum stefin A, IGFBP-3, c) positive immuno-staining of primary tumors for Her-2/neu, survivin and cathepsin B / stefin A ratio > 1 and d) gene expression of AMACR, HER-2/neu, high Bcl-2: Bax ratio and EZH2 in cancer cells. These markers have been chosen for review because they are among the most promising markers emerging currently.
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PMID:The importance of determining the aggressiveness of prostate cancer using serum and tissue molecular markers. 1840 43

Breast cancer remains the major cause of cancer-related deaths in women world-wide. The heterogeneity of breast cancer has further complicated the progress of target-based therapies. Triple negative breast cancers, lacking estrogen receptor, progesterone receptor and the Her-2/neu (ErbB2), represent a highly aggressive breast cancer subtype, that are difficult to treat. Pleiotropic agents, such as those found in nature, can target receptor-positive as well as receptor-negative cancer cells, suggesting that such agents could have significant impact in breast cancer prevention and/or therapy. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is one such agent which has anti-tumor activity against several cancers. However, its mechanism of action against breast cancer is not clearly understood. We hypothesized that plumbagin may act as an effective agent against breast cancer especially triple negative breast cancer. We tested our hypothesis using ER-positive MCF-7 and ER-negative MDA-MB-231 (triple negative) breast cancer cells, and we found that plumbagin significantly inhibits the growth of breast cancer cells with no effect on normal breast epithelial cells. We also found that plumbagin induces apoptosis with concomitant inactivation of Bcl-2 and the DNA binding activity of NF-kappaB. Bcl-2 over-expression resulted in attenuation of plumbagin-induced effects, suggesting that the inhibition of cell growth and induction of apoptosis by plumbagin is in part due to inactivation of NF-kappaB/Bcl-2 pathway. To our knowledge, this is the first report, showing mechanistic and cancer cell specific apoptosis-inducing effects of plumbagin in breast cancer cells, suggesting the potential role of plumbagin in the prevention and/or treatment of breast cancer.
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PMID:Plumbagin-induced apoptosis of human breast cancer cells is mediated by inactivation of NF-kappaB and Bcl-2. 1898 Feb 40

ErbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis or progression such as breast cancer and ovarian cancer. Our previous study showed that ON-III (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) extracted from Traditional Chinese Medicine Cleistocaly xoperculatus dry flower could inhibit KDR tyrosine kinase phosphorylation and tumor growth in vivo. In this study, we reported that ON-III repressed tyrosine phosphorylation of erbB-2 without reduced erbB-2 receptor expression in MDA-MB-453 cells. Activation of mitogen-activated protein kinase (MAPK) and AKT, downstream molecules of erbB-2-mediated signal transduction pathway, was inhibited following exposure to ON-III. ON-III induced apoptosis in breast cancer cells as determined by caspase-3 and PARP cleavage. Also, ON-III upregulated the expression of proapoptotic BH3-only Bcl-2 family member Bim. Bim siRNA could inhibit ON-III-mediated apoptosis in MDA-MB-453 cells. It concludes that ON-III inhibits erbB-2 tyrosine kinase phosphorylation, shuts down its downstream pathway and triggered apoptosis via induction of Bim. These results suggest that ON-III is a potential novel anti-cancer agent for erbB-2-overexpressing cancer.
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PMID:ON-III inhibits erbB-2 tyrosine kinase receptor signal pathway and triggers apoptosis through induction of Bim in breast cancer cells. 1924 12


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