Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNFalpha) mediates cytochrome c release from mitochondria, loss of mitochondrial membrane potential (DeltaPsim) and apoptosis in sensitive leukemic cells. In the present study, by using the human leukemic U937 cell line, we demonstrate that the cytochrome c release is caspase-8-dependent and can be blocked by an inhibitor of caspase-8, Z-Ile-Glu (OMe)-Thr-Asp(OMe)-fluoromethyl ketone (Z-IETD.fmk), or a pan caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD.fmk). However, TNFalpha-mediated loss of DeltaPsim was not inhibited by caspase inhibitors. The apoptotic process was blocked by either Z-IETD.fmk or Z-VAD.fmk in cells with lower DeltaPsim. U937 cells with stable transfection of the cellular inhibitor of apoptosis protein 1 (c-IAP1) are resistant to TNFalpha-induced activation of caspases, Bid cleavage, cytochrome c release and DeltaPsim collapse. In addition, both c-IAP1 and XIAP were not up-regulated upon prolonged exposure to TNFalpha. In contrast, there was a caspase-dependent cleavage of XIAP, but not c-IAP1, during treatment with TNFalpha for 7 days. These results demonstrate that c-IAP1 blocks TNFalpha signaling at a level controlling both activation of caspase-8 and a signal to cause loss of DeltaPsim. The sensitive U937 cell line failed to acquire resistance and gain a self-protecting advantage against apoptosis, upon induction of c-IAP1 expression.
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PMID:c-IAP1 blocks TNFalpha-mediated cytotoxicity upstream of caspase-dependent and -independent mitochondrial events in human leukemic cells. 1154 72

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, may be a good target for cancer therapy because it is expressed in a variety of human tumors but not in differentiated adult tissues. In the present study, we show that a combination of sulindac and arsenic trioxide (ATO) induces more extensive apoptosis than either drug alone in A549 human non-small cell lung carcinoma (NSCLC) cells. Treatment with sulindac/ATO reduced the expression of survivin and promoted major apoptotic signaling events, namely, collapse of the mitochondrial membrane potential, release of cytochrome c, and activation of caspases. Combined sulindac/ATO treatment did not significantly affect the levels of other members of the IAP family (XIAP, cIAP1 and cIAP2), indicating that the effects were specific to survivin. In addition, sulindac/ATO treatment induced the production of reactive oxygen species and the antioxidant N-acetyl-l-cysteine blocked the down-regulation of survivin and induction of apoptotic signaling by the combination of sulindac and ATO. Combined sulindac/ATO treatment also activated p53 expression, and inhibition of p53 expression by small interfering RNA (siRNA) prevented sulindac/ATO-induced down-regulation of survivin, suggesting that survivin expression is negatively regulated by p53. Overexpression of survivin reduced sulindac/ATO-induced apoptosis in A549 cells and reduction of survivin levels by siRNA sensitized the cells to sulindac/ATO-induced cell death. These results demonstrate that, in A549 human NSCLC cells, sulindac/ATO-induced apoptosis is mediated by the reactive oxygen species-dependent down-regulation of survivin.
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PMID:Synergistic induction of apoptosis by sulindac and arsenic trioxide in human lung cancer A549 cells via reactive oxygen species-dependent down-regulation of survivin. 1695 Feb 7

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