The Herbal Compound Cryptotanshinone Restores Sensitivity in Cancer Cells That Are Resistant to the Tumor Necrosis Factor-related Apoptosis-inducing Ligand

Tse, Anfernee Kai-Wing; Chow, Ka-Yu; Cao, Hongxin; Cheng, Chi-Yan; Kwan, Hiu Yee; Yu, Hua; Zhu, Guo‐Yuan; Wu, Yiu-Cheong; Fong, Wang‐Fun; Yu, Zhi‐Ling

doi:10.1074/jbc.m113.483909

Cited by 39 publications

(30 citation statements)

References 30 publications

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“…Similar with previous reports that CPT had antitumor function in vitro for many kinds of tumor cells (Park et al, 2013;Tse et al, 2013), our results also showed that CPT inhibited the proliferation of breast cancer cells (MCF7) in vitro. To further identify the antitumor activity of CPT in vivo, C57 mice all injected with 1×10 6 MCF7 cells, and then treated with CPT or Taxol since day 5, respectively.…”

Section: Cpt Inhibits Tumor Growth In Vivosupporting

confidence: 91%

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Zhou

Xu²,

Hu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibit tumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Using a mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo with polarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation, and also increased IFN-γ and perforin production of CD4+ T cells in response to tumor-activated splenocytes. Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogated by concanamycin A(CMA), a perforin inhibitor, but not IFN-γ Ab. On the other hand, after depletion of CD4+ T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumor growth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggested that CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin. We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, and demonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.

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Section: Cpt Inhibits Tumor Growth In Vivosupporting

confidence: 91%

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Zhou

Xu²,

Hu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Thus, recently several natural compounds such as quercetin [33], curcumin [34], artepillin C [35], azadirone [36], emetine [37], crytotanshinone [38] and salirasib [39] are attractive as TRAIL sensitizers in many cancers. In the current study, we provide evidences that Tanshinone I sensitizes the prostate cancer cells to TRAIL induced apoptosis via upregulation of miR 135a-3p mediated DR5.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis

et al. 2014

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Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer.

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“…In melanoma, these enclosed multiple kinase inhibitors targeting PKC (Gillespie et al, 2005), c-Kit (Hamai et al, 2006), IKK/NF-B , PI3K/Akt and MAP kinases . Also inhibitors of potassium channels (Quast et al, 2012;Suzuki et al, 2012), cellular metabolism (Liu et al, 2009;Qin et al, 2010), HDAC (Zhang et al, 2003) and COX-2 (Tse et al, 2014) were effective as well as natural compounds as picropodophyllin (Karasic et al, 2010), indirubin (Berger et al, 2011) and cryptotanshinone (Tse et al, 2013) or inorganic compounds as sodium arsenite (Ivanov and Hei, 2006;Ivanov and Hei, 2011). Due to this extremely high diversity, the pathways to melanoma sensitization for TRAIL remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins

Quast

Steinhorst

Plötz

et al. 2015

Journal of Investigative Dermatology

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The death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) represents a promising strategy for melanoma due to significant expression of TRAIL receptor 1 in melanoma metastases and high TRAIL sensitivity through this receptor. However, prevalent and inducible resistance are limiting its clinical use. In previous work, we and others have described multiple strategies leading to TRAIL sensitization; however, the common principles of these strategies remained elusive. Here, we demonstrate in melanoma cell lines (TRAIL-sensitive, TRAIL-resistant, and TRAIL-selected cells with acquired resistance) that cell cycle arrest clearly correlates with enhanced TRAIL sensitivity. Cell cycle arrest was induced by high cell confluence, serum starvation, or cyclin-dependent kinase (CDK) 4/6 inhibition. Addressing the signaling pathways revealed disruption of mitochondrial membrane potential and production of reactive oxygen species (ROS) in response to antiproliferative conditions alone. Activation of the proapoptotic Bcl-2 protein Bax and inhibition of apoptosis by Bcl-2 overexpression or by the antioxidant N-acetyl cysteine underlined the critical involvement of mitochondrial apoptosis pathways and of ROS, respectively. Most pronounced was the upregulation of small proapoptotic Bcl-2 proteins (Puma and Bcl-xS). These data provide a general understanding on TRAIL sensitization as well as an alternative view on CDK inhibitors and may suggest selective targeting of melanoma cells by cell cycle inhibition and TRAIL.

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The Herbal Compound Cryptotanshinone Restores Sensitivity in Cancer Cells That Are Resistant to the Tumor Necrosis Factor-related Apoptosis-inducing Ligand

Cited by 39 publications

References 30 publications

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis

Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins

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