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)

B16 melanoma (B16M) cells with high GSH content show high metastatic activity. However, the molecular mechanisms linking GSH to metastatic cell survival are unclear. The possible relationship between GSH and the ability of Bcl-2 to prevent cell death was studied in B16M cells with high (F10) and low (F1) metastatic potential. Analysis of a Bcl-2 family of genes revealed that B16M-F10 cells, as compared with B16M-F1 cells, overexpressed preferentially Bcl-2 (approximately 5.7-fold). Hepatic sinusoidal endothelium-induced B16M-F10 cytotoxicity in vitro increased from approximately 19% (controls) to approximately 97% in GSH-depleted B16M-F10 cells treated with an antisense Bcl-2 oligodeoxynucleotide (Bcl-2-AS). l-Buthionine (S,R)-sulfoximine-induced GSH depletion or Bcl-2-AS decreased the metastatic growth of B16M-F10 cells in the liver. However, the combination of l-buthionine (S,R)-sulfoximine and Bcl-2-AS abolished metastatic invasion. Bcl-2-overexpressing B16M-F1/Tet-Bcl-2 and B16M-F10/Tet-Bcl-2 cells, as compared with controls, showed an increase in GSH content, no change in the rate of GSH synthesis, and a decrease in GSH efflux. Thus, Bcl-2 overexpression may increase metastatic cell resistance against oxidative/nitrosative stress by inhibiting release of GSH. In addition, Bcl-2 availability regulates the mitochondrial GSH (mtGSH)-dependent opening of the permeability transition pore complex. Death in B16M-F10 cells was sharply activated at mtGSH levels below 30% of controls values. However, this critical threshold increased to approximately 60% of control values in Bcl-2-AS-treated B16M-F10 cells. GSH ester-induced replenishment of mtGSH levels (even under conditions of cytosolic GSH depletion) prevented cell death. Our results indicate that survival of B16M cells with high metastatic potential can be challenged by inhibiting their GSH and Bcl-2 synthesis.
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PMID:Down-regulation of glutathione and Bcl-2 synthesis in mouse B16 melanoma cells avoids their survival during interaction with the vascular endothelium. 1288 29

Highly metastatic B16 melanoma (B16M)-F10 cells, as compared with the low metastatic B16M-F1 line, have higher GSH content and preferentially overexpress BCL-2. In addition to its anti-apoptotic properties, BCL-2 inhibits efflux of GSH from B16M-F10 cells and thereby may facilitate metastatic cell resistance against endothelium-induced oxidative/nitrosative stress. Thus, we investigated in B16M-F10 cells which molecular mechanisms channel GSH release and whether their modulation may influence metastatic activity. GSH efflux was abolished in multidrug resistance protein 1 knock-out (MRP-/-1) B16M-F10 transfected with the Bcl-2 gene or in MRP-/-1 B16M-F10 cells incubated with l-methionine, which indicates that GSH release from B16M-F10 cells is channeled through MRP1 and a BCL-2-dependent system (likely related to an l-methionine-sensitive GSH carrier previously detected in hepatocytes). The BCL-2-dependent system was identified as the cystic fibrosis transmembrane conductance regulator, since monoclonal antibodies against this ion channel or H-89 (a protein kinase A-selective inhibitor)-induced inhibition of cystic fibrosis transmembrane conductance regulator gene expression completely blocked the BCL-2-sensitive GSH release. By using a perifusion system that mimics in vivo conditions, we found that GSH depletion in metastatic cells can be achieved by using Bcl-2 antisense oligodeoxynucleotide- and verapamil (an MRP1 activator)-induced acceleration of GSH efflux, in combination with acivicin-induced inhibition of gamma-glutamyltranspeptidase (which limits GSH synthesis by preventing cysteine generation from extracellular GSH). When applied under in vivo conditions, this strategy increased tumor cytotoxicity (up to approximately 90%) during B16M-F10 cell adhesion to the hepatic sinusoidal endothelium.
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PMID:Acceleration of glutathione efflux and inhibition of gamma-glutamyltranspeptidase sensitize metastatic B16 melanoma cells to endothelium-induced cytotoxicity. 1556 10

Inhibition of cancer growth by resveratrol (trans-3,5,4'-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.
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PMID:Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma. 1573 13

Mitochondrial glutathione (mtGSH) depletion increases sensitivity of Bcl-2-overexpressing B16 melanoma (B16M)-F10 cells (high metastatic potential) to tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress and death in vitro. In vivo, mtGSH depletion in B16M-F10 cells was achieved by feeding mice (where the B16M-F10 grew as a solid tumor in the footpad) with an L-glutamine (L-Gln)-enriched diet, which promoted in the tumor cells an increase in glutaminase activity, accumulation of cytosolic L-glutamate, and competitive inhibition of GSH transport into mitochondria. L-Gln-adapted B16M-F10 cells, isolated using anti-Met-72 monoclonal antibodies and flow cytometry-coupled cell sorting, were injected into the portal vein to produce hepatic metastases. In l-Gln-adapted invasive (iB16M-Gln+) cells, isolated from the liver by the same methodology and treated with TNF-alpha and an antisense Bcl-2 oligodeoxynucleotide, viability decreased to approximately 12%. iB16M-Gln+ cell death associated with increased generation of O2*- and H2O2, opening of the mitochondrial permeability transition pore complex, and release of proapoptotic molecular signals. Activation of cell death mechanisms was prevented by GSH ester-induced mtGSH replenishment. The oxidative stress-resistant survivors showed an adaptive response that includes overexpression of manganese-containing superoxide dismutase (Mn-SOD) and catalase activities. By treating iB16M-Gln+ cells with a double anti- antisense therapy (Bcl-2 and SOD2 antisense oligodeoxynucleotides) and TNF-alpha, metastatic cell survival decreased to approximately 1%. Chemotherapy (taxol plus daunorubicin) easily removed this minimum percentage of survivors. This contribution identifies critical molecules that can be sequentially targeted to facilitate elimination of highly resistant metastatic cells.
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PMID:Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. 1626 11

Intravenous administration to mice of trans-pterostilbene (t-PTER; 3,5-dimethoxy-4'-hydroxystilbene) and quercetin (QUER; 3,3',4',5,6-pentahydroxyflavone), two structurally related and naturally occurring small polyphenols, inhibits metastatic growth of highly malignant B16 melanoma F10 (B16M-F10) cells. t-PTER and QUER inhibit bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. However, the molecular mechanism(s) linking polyphenol signaling and bcl-2 expression are unknown. NO is a potential bioregulator of apoptosis with controversial effects on Bcl-2 regulation. Polyphenols may affect NO generation. Short-term exposure (60 min/day) to t-PTER (40 microM) and QUER (20 microM) (approximate mean values of the plasma concentrations measured within the first hour after intravenous administration of 20 mg of each polyphenol/kg) down-regulated inducible NO synthetase in B16M-F10 cells and up-regulated endothelial NO synthetase in the vascular endothelium and thereby facilitated endothelium-induced tumor cytotoxicity. Very low and high NO levels down-regulated bcl-2 expression in B16M-F10 cells. t-PTER and QUER induced a NO shortage-dependent decrease in cAMP-response element-binding protein phosphorylation, a positive regulator of bcl-2 expression, in B16M-F10 cells. On the other hand, during cancer and endothelial cell interaction, t-PTER- and QUER-induced NO release from the vascular endothelium up-regulated neutral sphingomyelinase activity and ceramide generation in B16M-F10 cells. Direct NO-induced cytotoxicity and ceramide-induced mitochondrial permeability transition and apoptosis activation can explain the increased endothelium-induced death of Bcl-2-depleted B16M-F10 cells.
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PMID:Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma. 1713 64

Capsaicin (8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient of hot chili peppers, has been reported to possess substantial anticarcinogenic and antimutagenic activities. In the present study, we investigated the effect of capsaicin on induction of apoptosis in highly metastatic B16-F10 murine melanoma cells. Capsaicin inhibited growth of B16-F10 cells in a concentration-dependent manner. Proapoptotic effect of capsaicin was evidenced by nuclear condensation, internucleosomal DNA fragmentation, in situ terminal nick-end labeling of fragmented DNA (TUNEL), and an increased sub G1 fraction. Treatment of B16-F10 cells with capsaicin caused release of mitochondrial cytochrome c, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase in a dose-dependent manner. Furthermore, Bcl-2 expression in the B16-F10 cells was slightly down-regulated by capsaicin treatment. In contrast, there were no alterations in the levels of Bax in capsaicin-treated cells. Collectively, these findings indicate that capsaicin-induces apoptosis of B16-F10 melanoma cells via down-regulation the Bcl-2.
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PMID:Capsaicin induced apoptosis of B16-F10 melanoma cells through down-regulation of Bcl-2. 1730 13

The treatment of cancer using macromolecular therapeutics such as oligonucleotides or peptides requires efficient delivery systems capable of intracellular penetration and may also benefit from use of a combination of therapeutics with different mechanisms of action. With this possibility in mind, we constructed cationic liposome loaded with the proapoptotic peptide, d-(KLAKLAK)(2) and the Bcl-2 antisense oligodeoxynucleotide, G3139, and determined whether the combination of the proapoptotic macromolecules in a single cationic liposome can enhance antitumor efficacy. Advantage was taken of alternating charge interaction to entrap macromolecules of opposite charge. The polycationic peptide d-(KLAKLAK)(2) was first condensed with the polyanionic oligodeoxynucleotide G3139 to obtain overall negatively charged peptide/oligodeoxynucleotide complexes. The complexes were then entrapped into DOTAP/DOPE cationic liposomes (CL). This sequential charge interaction ensured efficient entrapment of d-(KLAKLAK)(2) and G3139 with a high loading efficiency (50%) and capacity (7.5 wt %). In vitro treatment of mouse melanoma B16(F10) with CL loaded with d-(KLAKLAK)(2)/G3139 led to significantly enhanced antitumor efficacy, mediated by stimulated induction of apoptotic (caspase 3/7) activity, when compared to CL loaded with G3139 alone. Intratumoral injection of CL loaded with d-(KLAKLAK)(2)/G3139 in B16(F10) mice xenograft also led to suppressed tumor growth associated with enhanced apoptotic activity. Thus, the combination of proapoptotic peptide d-(KLAKLAK)(2) and antisense oligonucleotide G3139 in a cationic liposome led to enhanced apoptotic/antitumor efficacy and may provide a promising tool for cancer treatment.
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PMID:Cationic liposomes loaded with proapoptotic peptide D-(KLAKLAK)(2) and Bcl-2 antisense oligodeoxynucleotide G3139 for enhanced anticancer therapy. 1931 42

A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
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PMID:Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein. 2273 87

Melanoma is highly resistant to most conventional treatment, and the incidence and mortality rates are increasing rapidly worldwide. The objective of this study was to determine the anticancer effects of lobaplatin on the melanoma carcinoma cell line B16-F10 in vitro, and explored its mechanisms of action. Our results have shown that lobaplatin inhibited cell proliferation in human melanoma A375 and CHL-1 cells and murine melanoma B16-F10 cells in a concentration- and time-dependent manner. Flow cytometry assay confirmed that lobaplatin affected B16-F10 cell survival by blocking cell cycle progression in G2/M phase and inducing apoptosis in a concentration-dependent manner. In addition, the apoptosis was associated with downregulation of anti-apoptotic protein Bcl-2 while upregulation of pro-apoptotic protein Bax. Lobaplatin could also decrease the mitochondrial membrane potential, indicating that lobaplatin may induce apoptosis via mitochondria-mediated apoptotic pathway. Furthermore, lobaplatin blocked B16-F10 cell migration and invasion in vitro. These results suggested that lobaplatin could be an effective chemotherapeutic agent in melanoma treatment by inhibiting proliferation, inducing apoptosis, cell cycle arrest and blocking cell migration and invasion.
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PMID:Lobaplatin arrests cell cycle progression, induces apoptosis and impairs migration and invasion in B16-F10 melanoma cell line in vitro. 3162 61

The Bcl-2 family includes 26 proteins involved in apoptosis. Cancer cells can develop the ability to avoid apoptosis through the upregulation and/or down regulation of such proteins Bax, Bcl-xL or Mcl-1, especially during chemoresistance progress. These proteins engaged in a network of dynamic interactions that control apoptosis triggering have become attractive therapeutic targets in cancers including melanoma. Among them, the Bax/Bcl-xL interaction appears critical in maintaining mitochondria integrity. Therefore a series of mixed polyphenol-heterocyclic molecules, were rationally designed by molecular docking as Bax/Bcl-xL inhibitors. It has been screened against B16-F10 melanoma cancer cells for a preliminary investigation of their cytotoxicity. All these compounds exhibited a significant cytotoxicity against these cancer cells, in the 0.3-6 .M range. A pyrazole-type molecule, which had a submicromolar IC50 value with an excellent selectivity index (14), is the most promising derivative for further development.
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PMID:Preliminary Studies on the Activity of Mixed Polyphenol-Heterocyclic Systems Against B16-F10 Melanoma Cancer Cells. 2682 69


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