Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-X(L), survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII-positive blood vessels and hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-kappaB activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer.
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PMID:Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms. 1872 80

Chemoresistance in neuroblastoma is a significant issue complicating treatment of this common pediatric solid tumor. MYCN-amplified neuroblastomas are infrequently mutated at p53 and are chemosensitive at diagnosis but acquire p53 mutations and chemoresistance with relapse. Paradoxically, Myc-driven transformation is thought to require apoptotic blockade. We used the TH-MYCN transgenic murine model to examine the role of p53-driven apoptosis on neuroblastoma tumorigenesis and the response to chemotherapy. Tumors formed with high penetrance and low latency in p53-haploinsufficient TH-MYCN mice. Cyclophosphamide (CPM) induced a complete remission in p53 wild type TH-MYCN tumors, mirroring the sensitivity of childhood neuroblastoma to this agent. Treated tumors showed a prominent proliferation block, induction of p53 protein, and massive apoptosis proceeding through induction of the Bcl-2 homology domain-3-only proteins PUMA and Bim, leading to the activation of Bax and cleavage of caspase-3 and -9. Apoptosis induced by CPM was reduced in p53-haploinsufficient tumors. Treatment of MYCN-expressing human neuroblastoma cell lines with CPM induced apoptosis that was suppressible by siRNA to p53. Taken together, the results indicate that the p53 pathway plays a significant role in opposing MYCN-driven oncogenesis in a mouse model of neuroblastoma and that basal inactivation of the pathway is achieved in progressing tumors. This, in part, explains the striking sensitivity of such tumors to chemotoxic agents that induce p53-dependent apoptosis and is consistent with clinical observations that therapy-associated mutations in p53 are a likely contributor to the biology of tumors at relapse and secondarily mediate resistance to therapy.
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PMID:Chemotherapy-induced apoptosis in a transgenic model of neuroblastoma proceeds through p53 induction. 1895 36

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

Pharmacological manipulation of protein acetylation levels by histone deacetylase (HDAC) inhibitors represents a novel therapeutic strategy to treat neurodegeneration as well as cancer. However, the molecular mechanisms that determine how HDAC inhibition exerts a protective effect in neurons as opposed to a cytotoxic action in tumor cells has not been elucidated. We addressed this issue in cultured postnatal mouse cortical neurons whose p53-dependent and p53-independent intrinsic apoptotic programs require the proapoptotic multidomain protein, Bax. Despite promoting nuclear p53 accumulation, Class I/II HDAC inhibitors (HDACIs) protected neurons from p53-dependent cell death induced by camptothecin, etoposide, heterologous p53 expression or the MDM2 inhibitor, nutlin-3a. HDACIs suppressed p53-dependent PUMA expression, a critical signaling intermediate linking p53 to Bax activation, thus preventing postmitochondrial events including cleavage of caspase-9 and caspase-3. In human SH-SY5Y neuroblastoma cells, however, HDACIs were not able to prevent p53-dependent cell death. Moreover, HDACIs also prevented caspase-3 cleavage in postnatal cortical neurons treated with staurosporine, 3-nitropropionic acid and a Bcl-2 inhibitor, all of which require the presence of Bax but not p53 to promote apoptosis. Although these three toxic agents displayed a requirement for Bax, they did not promote PUMA induction. These results demonstrate that HDACIs block Bax-dependent cell death by two distinct mechanisms to prevent neuronal apoptosis, thus identifying for the first time a defined molecular target for their neuroprotective actions.
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PMID:Histone deacetylase inhibitors prevent p53-dependent and p53-independent Bax-mediated neuronal apoptosis through two distinct mechanisms. 1926 78

Dysregulation of apoptosis is a pilot event before cancer development and plays important roles for cancer to develop resistance to chemical therapeutics. So exploring strategies to recovery the apoptosis balance is a charming and long-endeavored aim in the attempts to conquer cancers. The present study shows an exciting potency of a fusion peptide to inhibit and target to cancer cells, which is composed of BH3 (Bcl-2 Homology 3) effector domain from PUMA (p53 upregulated modulator of apoptosis) and targeting domain of trans-activator of transcription (TAT) and DV3. The in vitro results demonstrated cancer growth inhibition by the fusion peptide in colon cancer cells, as well as in lung adenocarcinoma cell line and breast carcinoma cell line of human origin. But the viability of HEK293, a noncancerous cell line, was not affected, indicating the cancer specificity of the fusion peptide. Apoptosis activation was induced by the peptide through the mitochondria pathway. In vivo studies displayed its tumor inhibiting ability by intratumoral injection. When the fusion peptide was administered systematically by tail vein, the peptide targeted the established tumors in nude mice. No other organs were significantly involved. The fusion peptide is an artificially designed molecule worthy of further evaluation and development.
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PMID:BH3-based fusion artificial peptide induces apoptosis and targets human colon cancer. 1935 25

Nephrotoxicity is common with the use of the chemotherapeutic agent cisplatin, but the cellular mechanisms that modulate the extent of injury are unknown. Cisplatin downregulates expression of the taurine transporter gene (TauT) in LLC-PK1 proximal tubular renal cells, and forced overexpression of TauT protects against cisplatin-induced apoptosis in vitro. Because the S3 segments of proximal tubules are the sites of both cisplatin-induced injury and adaptive regulation of the taurine transporter, we hypothesized that TauT functions as an anti-apoptotic gene and protects renal cells from cisplatin-induced nephrotoxicity in vivo. Here, we studied the regulation of TauT in cisplatin nephrotoxicity in a human embryonic kidney cell line and in LLC-PK1 cells, as well as in TauT transgenic mice. Cisplatin-induced activation of p53 repressed TauT and overexpression of TauT prevented the progression of cisplatin-induced apoptosis and renal dysfunction in TauT transgenic mice. Although cisplatin activated p53 and PUMA (a p53-responsive proapoptotic Bcl-2 family protein) in the kidneys of both wildtype and TauT transgenic mice, only wildtype animals demonstrated acute kidney injury. These data suggest that functional TauT plays a critical role in protecting against cisplatin-induced nephrotoxicity, possibly by attenuating a p53-dependent pathway.
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PMID:Functional TauT protects against acute kidney injury. 1942 93

Parathyroid hormone (PTH) has a central role in the regulation of serum calcium and phosphate, whereas parathyroid hormone-related peptide (PTHrP) has important developmental roles. In addition, PTHrP has been discovered as a causative agent of hypercalcemia of malignancy. PTHrP is also expressed in many tumors, and expression often correlates with unfavorable prognosis. We have investigated the effects of PTHrP on apoptosis signaling pathways initiated by DNA damaging chemotherapeutic drugs. Stimulation experiments of the CD95-, the TNF-R-, and the TRAIL-R-death receptor systems in Saos human osteosarcoma cells revealed that PTHrP can block signaling via each of these death receptors. Furthermore, our findings demonstrate a link between PTHrP and the mitochondrial apoptosis pathway. PTHrP down-regulates expression of pro-apoptotic Bcl-2 family members like Bax and PUMA and up-regulates expression of antiapoptotic molecules like Bcl-2 and Bcl-xl. It is of clinical relevance that PTHrP and anticancer drugs show opposing interactions on death receptor-triggered as well as on mitochondrial apoptosis pathways. In addition, PTHrP induces chemoresistance by interference with p53 family-dependent apoptosis signaling pathways and p53-mediated transactivation of apoptosis target genes. Inhibition of CD95- and Bax gene transactivation is a mechanism by which PTHrP reduced the apoptosis response and treatment sensitivity of tumor cells. Our data indicate that PTHrP inhibits major apoptosis signaling pathways by blocking signaling via p53, death receptors and mitochondria and, consequently, confers chemoresistance of cancer cells. Thus, beyond its importance in development and differentiation, we describe an important role for PTHrP in tumorigenesis.
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PMID:Parathyroid hormone-related protein confers chemoresistance by blocking apoptosis signaling via death receptors and mitochondria. 1950 49

The purpose of this study was to examine whether histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; Zolinza/vorinostat) could sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant breast carcinoma in vivo. BALB/c nude mice were orthotopically implanted with TRAIL-resistant MDA-MB-468 cells and treated i.v. with SAHA, TRAIL, or SAHA followed by TRAIL for four times during first 3 weeks. The effects of drugs on tumor growth and markers of apoptosis, metastasis, and angiogenesis were examined. SAHA sensitized TRAIL-resistant xenografts to undergo apoptosis through multiple mechanisms. Whereas TRAIL alone was ineffective, SAHA inhibited growth of MDA-MB-468 xenografts in nude mice by inhibiting markers of tumor cell proliferation, angiogenesis, and metastasis and inducing cell cycle arrest and apoptosis. The sequential treatment of nude mice with SAHA followed by TRAIL was more effective in inhibiting tumor growth, angiogenesis, and metastasis and inducing apoptosis than SAHA alone, without overt toxicity. Treatment of nude mice with SAHA resulted in down-regulation of nuclear factor-kappaB and its gene products (cyclin D1, Bcl-2, Bcl-X(L), vascular endothelial growth factor, hypoxia-inducible factor-1alpha, interleukin-6, interleukin-8, matrix metalloproteinase-2, and matrix metalloproteinase-9) and up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa, PUMA, p21(CIP1), tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in tumor cells. Furthermore, control mice showing increased rate of tumor growth had increased numbers of CD31(+) or von Willebrand factor-positive blood vessels and increased circulating vascular endothelial growth factor receptor 2-positive endothelial cells compared with SAHA-treated or SAHA plus TRAIL-treated mice. In conclusion, sequential treatment with SAHA followed by TRAIL may target multiple pathways in tumor progression, angiogenesis, and metastasis and represents a novel therapeutic approach to treat breast cancer.
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PMID:Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice. 1950 67

Cervical carcinoma is a growing menace to women health worldwide. This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL-60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time-dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol-3-kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF-kappaB/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up-regulated PUMA, which concomitantly decreased the Bcl-2 level, caused mitochondrial membrane potential loss with attendant translocation of Bax and drp1 to mitochondria and release of pro-apoptotic factors such as cytochrome c and Smac/Diablo to cytosol leading to caspases-3 and -9 activation. In addition both the phospho-p53 and p21 were found to accumulate heavily in the nuclear fraction with attendant decrease in topoisomarase II and survivin levels. On the contrary, TPD did not affect the extrinsic signaling transduction pathway effectively through apical death receptors. Interestingly, N-acetyl cysteine, ascorbate and s-methylisothiourea (sMIT) rescued cells significantly from TPD induced DNA damage and caspases activation. TPD may thus find usefulness in managing and treating cervical cancer.
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PMID:Activation of p53/p21/PUMA alliance and disruption of PI-3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata. 1954 29

PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a critical mediator of p53-dependent and -independent apoptosis induced by a wide variety of stimuli, including genotoxic stress, deregulated oncogene expression, toxins, altered redox status, growth factor/cytokine withdrawal and infection. It serves as a proximal signaling molecule whose expression is regulated by transcription factors in response to these stimuli. PUMA transduces death signals primarily to the mitochondria, where it acts indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members. It directly binds and antagonizes all known antiapoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. PUMA ablation or inhibition leads to apoptosis deficiency underlying increased risks for cancer development and therapeutic resistance. Although elevated PUMA expression elicits profound chemo- and radiosensitization in cancer cells, inhibition of PUMA expression may be useful for curbing excessive cell death associated with tissue injury and degenerative diseases. Therefore, PUMA is a general sensor of cell death stimuli and a promising drug target for cancer therapy and tissue damage.
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PMID:PUMA, a potent killer with or without p53. 1964 8


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