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A promising "TRAIL" of tanshinones for cancer therapy.

Ho TF, Chang CC - Biomedicine (Taipei) (2015)

Bottom Line: Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL-induced apoptosis.Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers.In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, 406, Taichung, Taiwan.

ABSTRACT
An ideal cancer therapy specifically targets cancer cells while sparing normal tissues. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) elicits apoptosis by engaging its cognate death receptors (DRs-namely, DR4 and DR5. The cancer cell-selective proapoptotic action of TRAIL is highly attractive for cancer therapy, but clinical application of TRAIL is rather limited due to tumors' inherent or acquired TRAIL resistance. Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL-induced apoptosis. Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers. In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese). Research from our laboratories and others have revealed the synergy of a tanshinones-TRAIL combination in diverse types of cancer cells through up-regulation of DR5 and/or down-regulation of antiapoptotic proteins such as survivin. Thus, in addition to their anticancer mechanisms, tanshinones as TRAIL sensitizers hold great potential to be translated to TRAIL-based therapeutic modalities for combatting cancer.

No MeSH data available.


Related in: MedlinePlus

TRAIL-induced apoptosis signaling pathway. TRAIL initiatesapoptosis through binding to DR4 and/or DR5. TRAIL binding inducesreceptor trimerization to promote the assembly of DISC (composed of FADDand procaspases 8/10) to induce self-cleavage and thus activation ofcaspases 8/10, which in turn trigger downstream caspase cascade to executeapoptosis program. In certain cell types, activated caspase 8 cleaves BIDto generate truncated BID (tBID), which in turn triggers the mitochondrialapoptosis pathway. c-FLIP competes with procaspase 8 for recruitment toDISC, thereby suppressing activation of procaspase 8 and thus dampeningTRAIL-initiated apoptosis stimuli. Antiapoptotic BCL-2 family membersBCL-2, BCL-xL, and MCL-1 suppress the activation of the mitochondrialapoptosis pathway to blunt TRAIL-induced apoptosis. IAP proteins survivinand XIAP induce TRAIL resistance viathe blockade of the activity of executioner caspases.
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Fig4: TRAIL-induced apoptosis signaling pathway. TRAIL initiatesapoptosis through binding to DR4 and/or DR5. TRAIL binding inducesreceptor trimerization to promote the assembly of DISC (composed of FADDand procaspases 8/10) to induce self-cleavage and thus activation ofcaspases 8/10, which in turn trigger downstream caspase cascade to executeapoptosis program. In certain cell types, activated caspase 8 cleaves BIDto generate truncated BID (tBID), which in turn triggers the mitochondrialapoptosis pathway. c-FLIP competes with procaspase 8 for recruitment toDISC, thereby suppressing activation of procaspase 8 and thus dampeningTRAIL-initiated apoptosis stimuli. Antiapoptotic BCL-2 family membersBCL-2, BCL-xL, and MCL-1 suppress the activation of the mitochondrialapoptosis pathway to blunt TRAIL-induced apoptosis. IAP proteins survivinand XIAP induce TRAIL resistance viathe blockade of the activity of executioner caspases.

Mentions: TRAIL is a type II membrane protein belonging to the TNF death ligandsuperfamily, which also includes TNFα and Fas ligand (FasL/CD95L) [38]. TRAIL is unique in its ability to inducep53- independent apoptosis selectively in cancer cells while sparing normal cells,thus avoiding the adverse side effects frequently associated with currentchemotherapeutic agents. TRAIL induces apoptosis primarily through the deathreceptors (DRs)-mediated apoptotic pathway (Figure 4). Four membrane-bound TRAIL receptors, including DR4(TRAIL-R1), DR5 (TRAIL-R2), decoy receptor 1 (DcR1/TRAIL-R3) and DcR2 (TRAIL-R4),and one soluble receptor osteoprotegerin (OPG) share highly homologousextracellular TRAIL-binding domain. Both DR4 and DR5 are functional TRAILreceptors that carry the cytoplasmic death domain (DD) to transduceTRAIL-initiated apoptotic signals, whereas DcR1, DcR2 and OPG lack the cytoplasmicDD and therefore antagonize TRAIL’s proapoptotic action. The binding of TRAIL toDR4 or DR5 induces receptor trimerization and consequently clusters thecytoplasmic DDs to recruit Fas-associated death domain (FADD) and pro-caspases 8and 10 for the assembly of death-inducing signaling complex (DISC), leading toselfcleavage and thus activation of pro-caspases 8/10. Activated caspases 8/10 inturn initiate downstream caspase cascade to execute apoptosis program and, incertain types of cells, also evoke the mitochondrial apoptosis pathway through thetruncation of the BH3-only protein BID (tBID) for the efficient induction ofapoptosis [39].


A promising "TRAIL" of tanshinones for cancer therapy.

Ho TF, Chang CC - Biomedicine (Taipei) (2015)

TRAIL-induced apoptosis signaling pathway. TRAIL initiatesapoptosis through binding to DR4 and/or DR5. TRAIL binding inducesreceptor trimerization to promote the assembly of DISC (composed of FADDand procaspases 8/10) to induce self-cleavage and thus activation ofcaspases 8/10, which in turn trigger downstream caspase cascade to executeapoptosis program. In certain cell types, activated caspase 8 cleaves BIDto generate truncated BID (tBID), which in turn triggers the mitochondrialapoptosis pathway. c-FLIP competes with procaspase 8 for recruitment toDISC, thereby suppressing activation of procaspase 8 and thus dampeningTRAIL-initiated apoptosis stimuli. Antiapoptotic BCL-2 family membersBCL-2, BCL-xL, and MCL-1 suppress the activation of the mitochondrialapoptosis pathway to blunt TRAIL-induced apoptosis. IAP proteins survivinand XIAP induce TRAIL resistance viathe blockade of the activity of executioner caspases.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4664605&req=5

Fig4: TRAIL-induced apoptosis signaling pathway. TRAIL initiatesapoptosis through binding to DR4 and/or DR5. TRAIL binding inducesreceptor trimerization to promote the assembly of DISC (composed of FADDand procaspases 8/10) to induce self-cleavage and thus activation ofcaspases 8/10, which in turn trigger downstream caspase cascade to executeapoptosis program. In certain cell types, activated caspase 8 cleaves BIDto generate truncated BID (tBID), which in turn triggers the mitochondrialapoptosis pathway. c-FLIP competes with procaspase 8 for recruitment toDISC, thereby suppressing activation of procaspase 8 and thus dampeningTRAIL-initiated apoptosis stimuli. Antiapoptotic BCL-2 family membersBCL-2, BCL-xL, and MCL-1 suppress the activation of the mitochondrialapoptosis pathway to blunt TRAIL-induced apoptosis. IAP proteins survivinand XIAP induce TRAIL resistance viathe blockade of the activity of executioner caspases.
Mentions: TRAIL is a type II membrane protein belonging to the TNF death ligandsuperfamily, which also includes TNFα and Fas ligand (FasL/CD95L) [38]. TRAIL is unique in its ability to inducep53- independent apoptosis selectively in cancer cells while sparing normal cells,thus avoiding the adverse side effects frequently associated with currentchemotherapeutic agents. TRAIL induces apoptosis primarily through the deathreceptors (DRs)-mediated apoptotic pathway (Figure 4). Four membrane-bound TRAIL receptors, including DR4(TRAIL-R1), DR5 (TRAIL-R2), decoy receptor 1 (DcR1/TRAIL-R3) and DcR2 (TRAIL-R4),and one soluble receptor osteoprotegerin (OPG) share highly homologousextracellular TRAIL-binding domain. Both DR4 and DR5 are functional TRAILreceptors that carry the cytoplasmic death domain (DD) to transduceTRAIL-initiated apoptotic signals, whereas DcR1, DcR2 and OPG lack the cytoplasmicDD and therefore antagonize TRAIL’s proapoptotic action. The binding of TRAIL toDR4 or DR5 induces receptor trimerization and consequently clusters thecytoplasmic DDs to recruit Fas-associated death domain (FADD) and pro-caspases 8and 10 for the assembly of death-inducing signaling complex (DISC), leading toselfcleavage and thus activation of pro-caspases 8/10. Activated caspases 8/10 inturn initiate downstream caspase cascade to execute apoptosis program and, incertain types of cells, also evoke the mitochondrial apoptosis pathway through thetruncation of the BH3-only protein BID (tBID) for the efficient induction ofapoptosis [39].

Bottom Line: Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL-induced apoptosis.Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers.In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, 406, Taichung, Taiwan.

ABSTRACT
An ideal cancer therapy specifically targets cancer cells while sparing normal tissues. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) elicits apoptosis by engaging its cognate death receptors (DRs-namely, DR4 and DR5. The cancer cell-selective proapoptotic action of TRAIL is highly attractive for cancer therapy, but clinical application of TRAIL is rather limited due to tumors' inherent or acquired TRAIL resistance. Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL-induced apoptosis. Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers. In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese). Research from our laboratories and others have revealed the synergy of a tanshinones-TRAIL combination in diverse types of cancer cells through up-regulation of DR5 and/or down-regulation of antiapoptotic proteins such as survivin. Thus, in addition to their anticancer mechanisms, tanshinones as TRAIL sensitizers hold great potential to be translated to TRAIL-based therapeutic modalities for combatting cancer.

No MeSH data available.


Related in: MedlinePlus