Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apo2L/TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines that induces death of cancer cells but not normal cells. Its potent apoptotic activity is mediated through its cell surface death domain-containing receptors, DR4 and DR5. Apo2L/TRAIL interacts also with 3 "decoy" receptors that do not induce apoptosis, DcR1, DcR2, which lack functional death domains, and osteoprotegerin (OPG). The aim of our study was to investigate the cytotoxic activity of Apo2L/TRAIL on established osteogenic sarcoma cell lines (BTK-143, HOS, MG-63, SJSA-1, G-292 and SAOS2) and in primary cultures of normal human bone (NHB) cells. When used alone, Apo2L/TRAIL at 100 ng/ml for 24 hr induced greater than 80% cell death in only 1 (BTK-143) of the 6 osteogenic sarcoma cell lines. In contrast, Apo2L/TRAIL-resistant cells were susceptible to Apo2L/TRAIL-mediated apoptosis in the presence of the anticancer drugs, Doxorubicin (DOX), Cisplatin (CDDP) and Etoposide (ETP) but not Methotrexate (MTX) or Cyclophosphamide (CPM). Importantly, neither Apo2L/TRAIL alone nor in combination with any of these drugs affected primary normal human bone cells under equivalent conditions. Apo2L/TRAIL-induced apoptosis, and its augmentation by chemotherapy in the resistant cell lines was mediated through caspase-8 and caspase-3 activation. Furthermore, Apo2L/TRAIL-induced apoptosis and its augmentation by chemotherapy was effectively inhibited by caspase-8 zIETD-fmk and caspase-3 zDEVD-fmk protease inhibitors and by the pan-caspase inhibitor zVAD-fmk. The pattern of basal Apo2L/TRAIL receptor mRNA expression, or expression of the intracellular caspase inhibitor FLICE-inhibitory protein, FLIP, could not be readily correlated with resistance or sensitivity to Apo2L/TRAIL-induced apoptosis. However, the augmentation of Apo2L/TRAIL effects by chemotherapy was associated with drug-induced up-regulation of death receptors DR4 and DR5 mRNA and protein. No obvious correlation was seen between the expression of OPG mRNA or protein and susceptibility of cells to Apo2L/TRAIL-induced apoptosis. Stable over-expression of a dominant negative form of the Fas-associated death domain protein (FADD) in the Apo2L/TRAIL-sensitive BTK-143 cells completely inhibited Apo2L/TRAIL-induced cell death. Our results indicate that chemotherapy and Apo2L/TRAIL act synergistically to kill cancer cells but not normal bone-derived osteoblast-like cells, which has implications for future therapy of osteosarcoma.
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PMID:Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to Apo2L/TRAIL-induced apoptosis. 1199 38

Previous study has found that a new nitroxyl spin-labeled derivative of podophyllotoxin, 4-[4"-(2",2",6",6"-tetramethyl-1"-piperidinyloxy)amino]-4'-demethyl-epipodophyllotoxin (GP7), can induce apoptosis in human leukemia cells. However, there have been no studies about the effects of GP7 on osteosarcoma (OS) cells. Here, we observed the anti-OS effects of GP7 in mouse and human OS cells with the comparison of etoposide. GP7 and etoposide inhibited the proliferation of a panel of mouse and human OS cells in a concentration- or time-dependent manner, and the inhibitory effect of GP7 on the proliferation of mouse LM8 or human U2OS cells was 1.28- or 1.35-fold higher than that of etoposide. GP7 or etoposide augmented the anti-OS effects of methotrexate, adriamycin, cisplatin, or their combination, and the combined inhibitory effects of GP7 with MTX on the proliferation of LM8 cells was higher than those of etoposide with MTX. GP7 arrested the cell cycle in S phase but etoposide in G(2)/M phase. GP7 or etoposide induced sub-G(1) peak, apoptotic DNA fragmentation, activations of caspase-3, -8, -9, and DNA fragmentation factor, downregulation of Bcl-2 and Bcl-xL, upregulation of Bax and Bak, and cytochrome-c release from mitochondria in both mouse and human OS cells. GP7 or etoposide also induced endonuclease G translocation from mitochondria into cytosol in mouse cells. GP7- or etoposide-induced apoptotic DNA fragmentation of human OS cells was inhibited by the pan caspase inhibitor and caspase-9 inhibitor, not by caspase-8 inhibitor whereas it was not inhibited by the pan caspase inhibitor in mouse OS cells. Our findings indicate that GP7 is effective against mouse and human OS cells in vitro. The apoptotic DNA fragmentation in mouse OS cells may be mediated by caspase-independent pathway with the involvement of endonuclease G whereas in human OS cells by caspase-9-dependent pathway downstream of the cytochrome-c-initiated caspase cascade.
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PMID:Induction of apoptosis through caspase-independent or caspase-9-dependent pathway in mouse and human osteosarcoma cells by a new nitroxyl spin-labeled derivative of podophyllotoxin. 2343 60

Drug-induced organ toxicity is a frequently encountered obstacle in the field of medical practice that limits the use of numerous pharmacologically valuable drugs. Methotrexate (MTX)-induced organ toxicity is unfortunately the rate-limiting factor for its clinical application. In the current study, MTX injection induced significant renal and hepatic toxicities manifested on functional, biochemical, and histopathological scales. This was associated with a significant elevation in both renal and hepatic contents of TNF-related apoptosis-inducing ligand (TRAIL) and caspase-8, biomarkers of tissue apoptosis. Inline, immunohistochemical analysis confirmed that tissue increased expression of Ki67 as a biomarker of tissue regeneration in both organs. Tranilast (TRAN) is a small molecular weight anti-inflammatory and antiallergic agent. TRAN's coadministration with MTX in the current study induced a significant tissue recovery via modulation of TRAIL/caspase-8 signaling and modulation of apoptosis-induced tissue proliferation confirmed by quantification of Ki67 expression. In conclusion, TRAN can be proposed as an effective drug to attenuate MTX-induced organ toxicity via modulation of apoptosis-induced tissue proliferation pathway.
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PMID:Tranilast attenuates methotrexate-induced renal and hepatic toxicities: Role of apoptosis-induced tissue proliferation. 3204 1