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Marine Drugs Regulating Apoptosis Induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL).

Elmallah MI, Micheau O - Mar Drugs (2015)

Bottom Line: Marine biomass diversity is a tremendous source of potential anticancer compounds.Its selectivity for cancer cells has attracted much attention in oncology.This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, Helwan University, Ain Helwan, Cairo 11790, Egypt. mohamed_almallah@science.helwan.edu.eg.

ABSTRACT
Marine biomass diversity is a tremendous source of potential anticancer compounds. Several natural marine products have been described to restore tumor cell sensitivity to TNF-related apoptosis inducing ligand (TRAIL)-induced cell death. TRAIL is involved during tumor immune surveillance. Its selectivity for cancer cells has attracted much attention in oncology. This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

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Schematic representation of the main TRAIL signaling or regulator components targeted by conventional chemotherapies to restore TRAIL-induced apoptosis. Restoration of apoptosis induced by TRAIL in resistant tumor cells can be induced through restoration of DR4 and/or DR5 (1), caspase-8/10 (2), or Bax expression (3), or down-regulation of anti-apoptotic factors such as c-FLIP (2), Bcl-2 family proteins (Bcl-2, Mcl-1, or Bcl-xL (3)), and/or survivin or XIAP (4).
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marinedrugs-13-06884-f003: Schematic representation of the main TRAIL signaling or regulator components targeted by conventional chemotherapies to restore TRAIL-induced apoptosis. Restoration of apoptosis induced by TRAIL in resistant tumor cells can be induced through restoration of DR4 and/or DR5 (1), caspase-8/10 (2), or Bax expression (3), or down-regulation of anti-apoptotic factors such as c-FLIP (2), Bcl-2 family proteins (Bcl-2, Mcl-1, or Bcl-xL (3)), and/or survivin or XIAP (4).

Mentions: In addition to these non-functional receptors, or the lack of expression of the agonistic receptors DR4 or DR5 [37,38,39], resistance to TRAIL-induced cell death can arise in tumor cells owing to a large variety of events, including a loss of caspase-8 expression [40] or the overexpression of c-FLIP [41,42] (Figure 2), the main inhibitor of caspase-8 [43]. Viral and cellular dominant negative homologues of caspase-8 and caspase-10, coined v-FLIPs and c-FLIPs, respectively, have been discovered in the late 1990s [43,44]. Like caspase-8 and caspase-10 these inhibitors harbor two DEDs and as such, can be recruited within the TRAIL DISC (For recent reviews see, [41,45]). The long form of c-FLIP contains a caspase-like domain but this domain is devoid of caspase catalytic activity [43]. Owing to their ability to be co-recruited with caspase-8 within the DISC and to inhibit caspase-8 chain formation [46], self-processing and activation [47], c-FLIP isoforms are mostly associated with inhibition of apoptosis induced by ligands of the TNF family (Figure 3). It should be noted, however, that the long isoform of c-FLIP is also able to activate caspase-8 within the DISC [48,49] by mere dimerization in the absence of proteolytic activity [50]. However, activation of caspase-8 by this long isoform of c-FLIP does not lead to caspase-8 release to the cytosol and, thus, caspase-3 activation. Cells expressing high levels of this isoform are, thus, protected from apoptosis induced by ligands of the TNF family. Furthermore, increasing evidence suggests that c-FLIP isoforms can also inhibit other cell death machineries, including apoptosis induced by TLR3 [51], unfolded protein response [52], or chemotherapy [53,54,55].


Marine Drugs Regulating Apoptosis Induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL).

Elmallah MI, Micheau O - Mar Drugs (2015)

Schematic representation of the main TRAIL signaling or regulator components targeted by conventional chemotherapies to restore TRAIL-induced apoptosis. Restoration of apoptosis induced by TRAIL in resistant tumor cells can be induced through restoration of DR4 and/or DR5 (1), caspase-8/10 (2), or Bax expression (3), or down-regulation of anti-apoptotic factors such as c-FLIP (2), Bcl-2 family proteins (Bcl-2, Mcl-1, or Bcl-xL (3)), and/or survivin or XIAP (4).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663558&req=5

marinedrugs-13-06884-f003: Schematic representation of the main TRAIL signaling or regulator components targeted by conventional chemotherapies to restore TRAIL-induced apoptosis. Restoration of apoptosis induced by TRAIL in resistant tumor cells can be induced through restoration of DR4 and/or DR5 (1), caspase-8/10 (2), or Bax expression (3), or down-regulation of anti-apoptotic factors such as c-FLIP (2), Bcl-2 family proteins (Bcl-2, Mcl-1, or Bcl-xL (3)), and/or survivin or XIAP (4).
Mentions: In addition to these non-functional receptors, or the lack of expression of the agonistic receptors DR4 or DR5 [37,38,39], resistance to TRAIL-induced cell death can arise in tumor cells owing to a large variety of events, including a loss of caspase-8 expression [40] or the overexpression of c-FLIP [41,42] (Figure 2), the main inhibitor of caspase-8 [43]. Viral and cellular dominant negative homologues of caspase-8 and caspase-10, coined v-FLIPs and c-FLIPs, respectively, have been discovered in the late 1990s [43,44]. Like caspase-8 and caspase-10 these inhibitors harbor two DEDs and as such, can be recruited within the TRAIL DISC (For recent reviews see, [41,45]). The long form of c-FLIP contains a caspase-like domain but this domain is devoid of caspase catalytic activity [43]. Owing to their ability to be co-recruited with caspase-8 within the DISC and to inhibit caspase-8 chain formation [46], self-processing and activation [47], c-FLIP isoforms are mostly associated with inhibition of apoptosis induced by ligands of the TNF family (Figure 3). It should be noted, however, that the long isoform of c-FLIP is also able to activate caspase-8 within the DISC [48,49] by mere dimerization in the absence of proteolytic activity [50]. However, activation of caspase-8 by this long isoform of c-FLIP does not lead to caspase-8 release to the cytosol and, thus, caspase-3 activation. Cells expressing high levels of this isoform are, thus, protected from apoptosis induced by ligands of the TNF family. Furthermore, increasing evidence suggests that c-FLIP isoforms can also inhibit other cell death machineries, including apoptosis induced by TLR3 [51], unfolded protein response [52], or chemotherapy [53,54,55].

Bottom Line: Marine biomass diversity is a tremendous source of potential anticancer compounds.Its selectivity for cancer cells has attracted much attention in oncology.This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, Helwan University, Ain Helwan, Cairo 11790, Egypt. mohamed_almallah@science.helwan.edu.eg.

ABSTRACT
Marine biomass diversity is a tremendous source of potential anticancer compounds. Several natural marine products have been described to restore tumor cell sensitivity to TNF-related apoptosis inducing ligand (TRAIL)-induced cell death. TRAIL is involved during tumor immune surveillance. Its selectivity for cancer cells has attracted much attention in oncology. This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

Show MeSH
Related in: MedlinePlus