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)

Sulforaphane (SFN) is a biologically active compound extracted from cruciferous vegetables, and possessing potent anti-cancer and anti-inflammatory activities. Here, we show that tumor necrosis factor-alpha (TNF-alpha), in combination with a sub-toxic dose of SFN, significantly triggered apoptosis in TNF-alpha-resistant leukemia cells (THP-1, HL60, U937, and K562), which was associated with caspase activity and poly (ADP-ribose)-polymerase cleavage. We also report that SFN non-specifically inhibited TNF-alpha-induced NF-kappaB activation through the inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, and p65 nuclear translocation. This inhibition correlated with the suppression of NF-kappaB-dependent genes involved in anti-apoptosis (IAP-1, IAP-2, XIAP, Bcl-2, and Bcl-xL), cell proliferation (c-Myc, COX-2, and cyclin D1), and metastasis (VEGF and MMP-9). These effects suggest that SFN inhibits TNF-alpha-induced NF-kappaB activation through the suppression of IkappaBalpha degradation, leading to reduced expression of NF-kappaB-regulated gene products. Combined treatment with SFN and TNF-alpha was also accompanied by the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine significantly attenuated the combined treatment-induced ROS generation and caspase-3-dependent apoptosis, implying the involvement of ROS in this type of cell death. In conclusion, the results of the present study indicate that SFN suppresses TNF-alpha-induced NF-kappaB activity and induces apoptosis through activation of ROS-dependent caspase-3.
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PMID:Sulforaphane suppresses TNF-alpha-mediated activation of NF-kappaB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3. 1895 68

Picroliv, an iridoid glycoside derived from the plant Picrorhiza kurroa, is used traditionally to treat fever, asthma, hepatitis, and other inflammatory conditions. However, the exact mechanism of its therapeutic action is still unknown. Because nuclear factor-kappaB (NF-kappaB) activation plays a major role in inflammation and carcinogenesis, we postulated that picroliv must interfere with this pathway by inhibiting the activation of NF-kappaB-mediated signal cascade. Electrophoretic mobility shift assay showed that pretreatment with picroliv abrogated tumor necrosis factor (TNF)-induced activation of NF-kappaB. The glycoside also inhibited NF-kappaB activated by carcinogenic and inflammatory agents, such as cigarette smoke condensate, phorbol 12-myristate 13-acetate, okadaic acid, hydrogen peroxide, lipopolysaccharide, and epidermal growth factor. When examined for the mechanism of action, we found that picroliv inhibited activation of IkappaBalpha kinase, leading to inhibition of phosphorylation and degradation of IkappaBalpha. It also inhibited phosphorylation and nuclear translocation of p65. Further studies revealed that picroliv directly inhibits the binding of p65 to DNA, which was reversed by the treatment with reducing agents, suggesting a role for a cysteine residue in interaction with picroliv. Mutation of Cys(38) in p65 to serine abolished this effect of picroliv. NF-kappaB inhibition by picroliv leads to suppression of NF-kappaB-regulated proteins, including those linked with cell survival (inhibitor of apoptosis protein 1, Bcl-2, Bcl-xL, survivin, and TNF receptor-associated factor 2), proliferation (cyclin D1 and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (intercellular adhesion molecule-1 and matrix metalloproteinase-9). Suppression of these proteins enhanced apoptosis induced by TNF. Overall, our results show that picroliv inhibits the NF-kappaB activation pathway, which may explain its anti-inflammatory and anticarcinogenic effects.
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PMID:Modification of cysteine residue in p65 subunit of nuclear factor-kappaB (NF-kappaB) by picroliv suppresses NF-kappaB-regulated gene products and potentiates apoptosis. 3018 11

Identification of active principles and their molecular targets from traditional medicine is an enormous opportunity for modern drug development. Gum resin from Commiphora wightii (syn C. mukul) has been used for centuries in Ayurveda to treat internal tumors, obesity, liver disorders, malignant sores and ulcers, urinary complaints, intestinal worms, leucoderma (vitiligo), sinuses, edema and sudden paralytic seizures. Guggulsterone has been identified as one of the major active components of this gum resin. This steroid has been shown to bind to the farnesoid X receptor and modulate expression of proteins with antiapoptotic (IAP1, XIAP, Bfl-1/A1, Bcl-2, cFLIP, survivin), cell survival, cell proliferation (cyclin D1, c-Myc), angiogenic, and metastatic (MMP-9, COX-2, VEGF) activities in tumor cells. Guggulsterone mediates gene expression through regulation of various transcription factors, including NF-kappaB, STAT-3 and C/EBPalpha, and various steroid receptors such as androgen receptor and glucocorticoid receptors. Modulation of gene expression by guggulsterone leads to inhibition of cell proliferation, induction of apoptosis, suppression of invasion and abrogation of angiogenesis. Evidence has been presented to suggest that guggulsterone can suppress tumor initiation, promotion and metastasis. This review describes the identification of molecular targets of guggulsterone, cellular responses to guggulsterone, and animal studies and clinical trials of guggulsterone in cancer and other diseases.
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PMID:The guggul for chronic diseases: ancient medicine, modern targets. 1918 46

We examine the possible evidence that the phytochemical curcumin may overcome resistance to hormonal and cytotoxic agents in breast cancer. We present our observations on MCF-7R, a multidrug-resistant (MDR) variant of the MCF-7 breast cancer cell line. In contrast to MCF-7, MCF-7R lacks aromatase and estrogen receptor alpha (ERalpha) and overexpresses the multidrug transporter ABCB1 and the products of different genes implicated in cell proliferation and survival, like c-IAP-1, NAIP, survivin, and COX-2. Nevertheless, in cytotoxicity and cell death induction assays, we found that the antitumor activity of curcumin is substantial both in MCF-7 and in MCF-7R. We elaborated the diketone system of curcumin into different analogues; the benzyloxime and the isoxazole and pyrazole heterocycles showed remarkable increases in the antitumor potency both in the parental and in the MDR MCF-7 cells. Furthermore, curcumin or, more potently, the isoxazole analogue, produced early reductions in the amounts of relevant gene transcripts that were diverse (i.e., they were relative to Bcl-2 and Bcl-X(L) in MCF-7 and the inhibitory of apoptosis proteins and COX-2 in MCF-7R) in the two cell lines. Thus, the two compounds exhibited the remarkable property of being able to modify their molecular activities according to the distinct characteristics of the parental and MDR cells. We discuss also how curcumin may (1) exert antitumor effects in breast cancer through ER-dependent and ER-independent mechanisms; and (2) act as a drug transporter-mediated MDR reversal agent. Overall, the structure of curcumin may represent the basis for the development of new, effective anticancer agents in hormone-independent MDR breast cancer.
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PMID:Curcumin as a possible lead compound against hormone-independent, multidrug-resistant breast cancer. 1925 Feb 17

Ginsenoside Rg3, the main constituent isolated from Panax ginseng, has been of interest for use as a cancer preventive or therapeutic agent. We investigated here whether Rg3 can inhibit the activity of NF-kappaB, a key transcriptional factor constitutively activated in colon cancer that confers cancer cell resistance to chemotherapeutic agents. To investigate whether RG3 can suppress activation of NF-kappaB, and thus inhibit cancer cell growth, we examined the susceptibility of colon cancer cells (SW620 and HCT116) to treatment with Rg3 (25, 50, 75, 100 microM) and RG3-induced activation of NF-kappaB. RG3 dose-dependently inhibited cancer cell growth through induction of apoptosis and decreased NF-kappaB activity. In a further study of compounds in colon cancer, we used half of the IC(50) dose, values in combined treatments of Rg3 (50 microM) with conventional agents - docetaxel (5 nM), paclitaxel (10 nM) cisplatin (10 microM) and doxorubicin (2 microM). Compared to treatment with Rg3 or chemotherapy alone, combined treatment was more effective (i.e., there were synergistic effects) in the inhibition of cancer cell growth and induction of apoptosis and these effects were accompanied by significant inhibition of NF-kappaB activity. NF-kappaB target gene expression of apoptotic cell death proteins (Bax, caspase-3, caspase-9) was significantly enhanced, but the expression of anti-apoptotic genes and cell proliferation marker genes (Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP), Cox-2, c-Fos, c-Jun and cyclin D1) was significantly inhibited by the combined treatment compared to Rg3 or docetaxel alone. These results indicate that ginsenoside Rg3 inhibits NF-kappaB, and enhances the susceptibility of colon cancer cells to docetaxel and other chemotherapeutics. Thus, ginsenoside Rg3 could be useful as an anti-cancer or adjuvant anti-cancer agent.
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PMID:Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. 1947 91

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.
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PMID:Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? 1959 Sep 64

Because tumor necrosis factor-alpha (TNF-alpha) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-alpha-induced NF-kappaB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-alpha-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-alpha-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-kappaB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-alpha was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-kappaB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-alpha-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-alpha-induced ROS generation and NF-kappaB activation, and enhances TNF-alpha-induced apoptosis.
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PMID:Rosmarinic acid sensitizes cell death through suppression of TNF-alpha-induced NF-kappaB activation and ROS generation in human leukemia U937 cells. 1961 38

N(alpha)-tosyl-L-phenylalanine chloromethylketone (TPCK) has been widely used to investigate signal transduction pathways that are involved in gene expression and cell survival/cell death. However, contradictory effects of TPCK on apoptosis have been reported, and the underlying signaling events leading to TPCK-induced promotion or prevention of apoptosis are not fully understood. Here, we show that TPCK induces caspase-dependent apoptosis in Epstein-Barr virus (EBV)-transformed human B cell lines with release of pro-apoptotic proteins from mitochondria. TPCK treatment also results in down-regulation of the anti-apoptotic proteins, cIAP1, cIAP2, and HAX-1, and caspase-dependent cleavage of the anti-apoptotic proteins, Bcl-2 and XIAP. Quantitative PCR analysis confirmed that the TPCK-induced down-regulation of HAX-1 occurred at the transcriptional level, and experiments using the specific pharmacological inhibitor, Bay 11-7082, suggested that HAX-1 expression is subject to regulation by the transcription factor, NF-kappaB. B cell lines derived from patients with homozygous HAX1 mutations were more sensitive to TPCK-induced apoptosis when compared with normal donor cell lines. Furthermore, N-acetylcysteine effectively blocked TPCK-induced apoptosis in EBV-transformed B cell lines and prevented the down-regulation or cleavage of anti-apoptotic proteins. Taken together, our studies demonstrate that TPCK induces apoptosis in human B cell lines and exerts multiple effects on pro- and anti-apoptotic factors.
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PMID:N(alpha)-tosyl-L-phenylalanine chloromethyl ketone induces caspase-dependent apoptosis in transformed human B cell lines with transcriptional down-regulation of anti-apoptotic HS1-associated protein X-1. 1967 60

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

Lamellarin D, a potent cytotoxic marine alkaloid, exerts its antitumor action through two complementary pathways: a nuclear route via topoisomerase I inhibition and a mitochondrial targeting. The present study was designed to investigate the contribution of these two pathways for apoptosis in cancer cells. Lamellarin D promoted nuclear apoptosis in leukemia cells without prominent cell cycle arrest. Signals transmitted by lamellarin D initiated apoptosis via the intrinsic apoptotic pathway. The drug induced conformational activation of Bax and decreased the expression levels of antiapoptotic proteins Bcl-2 and cIAP2 in association with activation of caspase-9 and caspase-3. Upon lamellarin D exposure, Fas and Fas-L expression was not modified in leukemia cells. Moreover, leukemia cells deficient in caspase-8 or Fas-associated protein with death domain underwent apoptosis through the typical mitochondrial apoptotic cascade, indicating that cell death induced by lamellarin D was independent of the extrinsic apoptotic pathway. Lamellarin D also exerted a topoisomerase I-mediated DNA damage response resulting in H2AX phosphorylation, and the upregulation of the DNA repair protein Rad51 and of p53, as well as the phosphorylation of p53 at serine 15. However, lamellarin D killed efficiently mutated p53 or p53 null cancer cells, and sensitivity to lamellarin D was abrogated neither by cycloheximide nor in enucleated cells. Lamellarin D-induced cytochrome c release occurs independently of nuclear factors in a cell-free system. These results suggest that lamellarin D exerts its cytotoxic effects primarily by inducing mitochondrial apoptosis independently of nuclear signaling. Thus, lamellarin D constitutes a new proapoptotic agent that may bypass certain forms of apoptosis resistance that occur in tumor cells.
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PMID:Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D. 1995 18


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