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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

The mechanisms underlying tanshinone IIA-TRAIL synergy.Tanshinone IIA sensitizes TRAIL-resistant epithelial ovarian cancer (EOC)cells to TRAIL-induced apoptosis through at least two mechanisms. First,tanshinone IIA evokes ROS-dependent activation of JNK to increase CHOPexpression, which in turn activate DR5transcription to up-regulate cell-surface DR5 levels for the potentiationof TRAIL-induced apoptosis stimuli. Second, tanshinone IIA engages the p38MAPK-mediated pathway to induce transcriptional down-regulation ofsurvivin, consequently promoting caspase activities to executeapoptosis.
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Fig5: The mechanisms underlying tanshinone IIA-TRAIL synergy.Tanshinone IIA sensitizes TRAIL-resistant epithelial ovarian cancer (EOC)cells to TRAIL-induced apoptosis through at least two mechanisms. First,tanshinone IIA evokes ROS-dependent activation of JNK to increase CHOPexpression, which in turn activate DR5transcription to up-regulate cell-surface DR5 levels for the potentiationof TRAIL-induced apoptosis stimuli. Second, tanshinone IIA engages the p38MAPK-mediated pathway to induce transcriptional down-regulation ofsurvivin, consequently promoting caspase activities to executeapoptosis.

Mentions: Down-regulation of IAPs such as survivin or XIAP represents an alternativeapproach to overcome TRAIL resistance aside from DR5 up-regulation [42]. Survivin is recognized as an attractivedrug target owing to its selective expression in malignant cells [61]. Notably, high levels of survivin have beenassociated with TRAIL resistance [62]. Along this line, we have revealed that tanshinone IIA inducesp38 MAPK-dependent transcriptional repression of survivin in TRAIL-resistant butnot TRAIL-sensitive human EOC cell lines [23]. Of note, ectopic survivin expression to counteracttanshinone IIA-induced survivin reduction markedly attenuates the synergisticcytotoxicity of the tanshinone IIATRAIL combination, indicating survivindown-regulation as an important mode of action for transhinone IIA to overcomeTRAIL resistance. Collectively, these findings have delineated that multiplemechanisms of action, including DR5 induction and survivin repression, areinvolved in the tanshinone IIA-mediated sensitization of TRAIL-resistant human EOCcells to TRAIL-induced apoptosis (Figure 5).


A promising "TRAIL" of tanshinones for cancer therapy.

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

The mechanisms underlying tanshinone IIA-TRAIL synergy.Tanshinone IIA sensitizes TRAIL-resistant epithelial ovarian cancer (EOC)cells to TRAIL-induced apoptosis through at least two mechanisms. First,tanshinone IIA evokes ROS-dependent activation of JNK to increase CHOPexpression, which in turn activate DR5transcription to up-regulate cell-surface DR5 levels for the potentiationof TRAIL-induced apoptosis stimuli. Second, tanshinone IIA engages the p38MAPK-mediated pathway to induce transcriptional down-regulation ofsurvivin, consequently promoting caspase activities to executeapoptosis.
© Copyright Policy
Related In: Results  -  Collection

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

Fig5: The mechanisms underlying tanshinone IIA-TRAIL synergy.Tanshinone IIA sensitizes TRAIL-resistant epithelial ovarian cancer (EOC)cells to TRAIL-induced apoptosis through at least two mechanisms. First,tanshinone IIA evokes ROS-dependent activation of JNK to increase CHOPexpression, which in turn activate DR5transcription to up-regulate cell-surface DR5 levels for the potentiationof TRAIL-induced apoptosis stimuli. Second, tanshinone IIA engages the p38MAPK-mediated pathway to induce transcriptional down-regulation ofsurvivin, consequently promoting caspase activities to executeapoptosis.
Mentions: Down-regulation of IAPs such as survivin or XIAP represents an alternativeapproach to overcome TRAIL resistance aside from DR5 up-regulation [42]. Survivin is recognized as an attractivedrug target owing to its selective expression in malignant cells [61]. Notably, high levels of survivin have beenassociated with TRAIL resistance [62]. Along this line, we have revealed that tanshinone IIA inducesp38 MAPK-dependent transcriptional repression of survivin in TRAIL-resistant butnot TRAIL-sensitive human EOC cell lines [23]. Of note, ectopic survivin expression to counteracttanshinone IIA-induced survivin reduction markedly attenuates the synergisticcytotoxicity of the tanshinone IIATRAIL combination, indicating survivindown-regulation as an important mode of action for transhinone IIA to overcomeTRAIL resistance. Collectively, these findings have delineated that multiplemechanisms of action, including DR5 induction and survivin repression, areinvolved in the tanshinone IIA-mediated sensitization of TRAIL-resistant human EOCcells to TRAIL-induced apoptosis (Figure 5).

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