Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous studies conducted in pancreatic cancer models established in nude mice and hamsters revealed that cloned somatostatin receptor subtype 2 (sst2) gene expression induced both antioncogenic and local antitumor bystander effects in vivo. In the present study, in vivo gene transfer of sst2 was investigated in two transplantable models of primary and metastatic pancreatic carcinoma developed in hamsters. LacZ reporter or mouse sst2 genes were expressed by means of two different delivery agents: an adenoviral vector and a synthetic polycationic carrier [linear polyethylenimine (PEI)]. sst2 was injected into either exponentially growing pancreatic primary tumors or hepatic metastases, and then transgene expression and tumor progression were investigated 5-6 days after gene transfer. Molecular mechanisms involved in the inhibition of tumor growth were also analyzed. Both adenovirus- and PEI-mediated in vivo gene transfer in primary pancreatic tumors induced an increase of beta-galactosidase activity and expression of sst2 transgene nRNA (100% and 86% of tumors for adenovirus and PEI vector, respectively). Adenoviral vector-based sst2 gene transfer resulted in significant reduction of pancreatic tumor growth (P < 0.05). Using PEI vector, both pancreatic primary tumor growth and metastatic tumor growth were also significantly slackened as compared with both LacZ-treated and untreated control groups (P < 0.02). Moreover, the proliferative index decreased significantly (P < 0.005), whereas apoptosis increased (P < 0.005) in tumors transferred with sst2 gene. The increase of apoptosis correlated with an activation of the caspase-3 and poly(ADP-ribose) polymerase pathways. We concluded that in both primary and metastatic pancreatic cancer models, the synthetic gene delivery system can achieve in vivo sst2 gene transfer and results in a significant antitumor effect characterized by an increase of apoptosis and an inhibition of cell proliferation. This new strategy of gene therapy allows the restoration of expression of an antioncogenic molecule and could be promising for the treatment of advanced pancreatic cancer.
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PMID:Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models. 1241 37

Benzyl isothiocyanate can exert anti-tumor effect by arrest of cell cycle progression and induction of apoptosis in human pancreatic cancer cells. Among them, the dissection of the molecular mechanism of induction of apoptosis is important because the knowledge may be exploited for both cancer prevention and treatment. Our studies reported here indicate that BITC-mediated apoptosis involves the disappearance of intact 21-kDa Bid protein, cytochrome c release and predominant procaspase-3 cleavage. Using adenocarcinoma and metastatic pancreatic cancer cells, we investigated whether this dietary isothiocyanate induces apoptosis by converging two major pathways: the death receptor-mediated extrinsic and the mitochondrial intrinsic pathway. Indeed, cell surface receptor analysis by flow cytometry demonstrates the up-regulation of DR4, a member of death receptor family in BITC exposed pancreatic cancer cells. Since BITC is able to trigger death receptor signaling, we were interested in examining the effects of BITC and death receptor ligand TRAIL together on pancreatic cancer cell death. Interestingly, BITC augments TRAIL-induced apoptosis in both metastatic and adenocarcinoma cells. Moreover, we report for the first time that the sensitivity of metastatic pancreatic cancer cells to this isothiocyanate might be due to down-modulation of the proangiogenic molecule small GTPase Rac1 and caspase-3 substrate RasGAP, a regulator of Rho GTPase family.
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PMID:Anti-proliferative and proapoptotic effects of benzyl isothiocyanate on human pancreatic cancer cells is linked to death receptor activation and RasGAP/Rac1 down-modulation. 1963 79

Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase/Akt and mTOR signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G(2)/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis, a mechanism-mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and gemcitabine resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies showed that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by Western blot analyses. There was also a downregulation of VEGF and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis.
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PMID:CDK-4 inhibitor P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis. 2253 2