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)

TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) is a major cytotoxic mechanism employed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to eradicate malignant cells. TRAIL/Apo2L interacts with its cognate receptors located on tumor cell surface namely, TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and osteoprotegerin (OPG). The exact function of DcR1 and DcR2 remains elusive. TRAIL/Apo2L or agonistic monoclonal antibodies directed against TRAIL/Apo2L death-inducing receptors (DR4, DR5) have become an attractive immunological therapeutic tools in clinical oncology due to their selective killing of tumors and lack of affinity towards healthy cells. Though a potent anti-cancer modality, some cancer cells exhibit inherent or acquired resistance to TRAIL/Apo2L. Postulated resistance mechanisms include up-regulation of c-FLIP, down-regulation of caspase-8, down-regulation/shedding of death receptors and an imbalanced ratio of pro- to anti-apoptotic genes due to aberrant activity of cellular survival signal transduction pathways. The development of resistance has spurred the use of combination therapy, in particular using small molecule sensitizing agents, to restore apoptosis sensitivity. A novel category of such compounds is histone deacetylase inhibitors (HDACi), which block HDACs from removing acetyl groups from histone tails thereby preventing silencing of pro-apoptotic genes and regulating the expression of non-histone proteins (i.e., apoptosis-associated genes), are effective agents in some malignancies. Some HDACi, such as Suberoylanilide Hydroxamic Acid (SAHA), have received FDA approval for cancer treatment. In various melanoma preclinical models, HDACi in conjunction with TRAIL/Apo2L, via modulation of apoptotic machinery, have proven to overcome acquired/inherent resistance to either agent. Here, we discuss recent findings on the role of TRAIL/Apo2L and its agonistic mAbs in melanoma immunotherapy with discussions on potential cellular and molecular events by which HDACi can sensitize metastatic melanoma to TRAIL/Apo2L-mediated immune-therapy, thereby, overcoming resistance.
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PMID:Epigenetic regulation of the TRAIL/Apo2L apoptotic pathway by histone deacetylase inhibitors: an attractive approach to bypass melanoma immunotherapy resistance. 2388 25

Galbanic acid (GBA) is known a sesquiterpene coumarin to have apoptotic, anti-hypoxic, anti-proliferative, anti-hepatitis, anti-angiogenic, anti-bacteria and anti-thrombotic effects. Also, antitumor effect of GBA was reported in prostate, ovary, breast and lung cancers. Nevertheless, the underlying molecular mechanism of GBA was not fully understood to overcome chemoresistance in resistant lung cancer so far. Thus, synergistic antitumor mechanism of GBA and TNF-related apoptosis-inducing ligand (TRAIL) was elucidated in H460 and resistant H460/R non-small cell lung cancer cells (NSCLCs). Combination of GBA and TRAIL significantly exerted cytotoxicity in a dose dependent manner compared to GBA or TRAIL alone in H460/R cells. Also, GBA and TRAIL significantly increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub-G1 population in a dose dependent manner in H460/R cells. Consistently, GBA and TRAIL induced cleavages of poly (ADP-ribose) polymerase (PARP), caspase-9 and caspase-8 along with upregulation of death receptor 5 (DR5) and also attenuated the expression of B-cell lymphoma-extra-large (Bcl-xL), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP) in H460/R cells. Furthermore, combination of GBA and TRAIL remarkably inhibited the expression of decoy receptor 1 (DcR1) and multidrug resistance 1(MDR1) in H460/R cells. Consistently, GBA and TRAIL effectively maintained Rhodamine 123 accumulation in H460/R cells compared to GBA or TRAIL alone by blocking multidrug efflux pump from the cells. Overall, our findings suggest that galbanic acid enhances TRAIL induced apoptosis via inhibition of MDR1 and activation of caspases and DR5 in H460/R cells as a potent TRAIL sensitizer.
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PMID:Galbanic acid potentiates TRAIL induced apoptosis in resistant non-small cell lung cancer cells via inhibition of MDR1 and activation of caspases and DR5. 3068 98


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