Triptolide and Chemotherapy Cooperate in Tumor Cell Apoptosis

Chang, Wenteh; Kang, Jason; Lee, Kye-Young; Wei, Ke; Anderson, Emily M.; Gotmare, Sonali; Ross, Jessica A.; Rosen, Glenn D.

doi:10.1074/jbc.m009713200

Cited by 156 publications

(104 citation statements)

References 24 publications

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“…Although several intracellular pathways such as the modification of nuclear factor-kB, Bcl-2, phosphatidylinositol-3 kinase, cyclins and c-myc have been reported to be responsible for the mechanisms underlying the action of triptolide (Lee et al, 1999;Chang et al, 2001;Jiang et al, 2001;Fidler et al, 2003;Yang et al, 2003;Miyata et al, 2005;Yinjun et al, 2005;Carter et al, 2006;Wan et al, 2006), our results showed that the attenuation of p53-dependent p21 induction was a key mechanism to enhance CDDP-induced cytotoxicity. Several recent studies have demonstrated that p53-dependent p21 induction inhibits the apoptotic response, and p21 attenuation may make genotoxic chemotherapeutic agents more effective by subverting the normal repair process or, more directly, by promoting the apoptotic process through inhibition of p21 interaction with apoptosis signal-regulating kinase 1, which is upstream of JNK (Asada et al, 1999;Gartel and Tyner, 2002;Weiss, 2003).…”

Section: Discussionmentioning

confidence: 46%

“…Concerning the detailed mechanism of triptolide to modulate p53 transcriptional activity, Chang et al (2001) previously reported that the phosphorylation of p53 induced by triptolide may be responsible. Our results, however, showed that intranuclear association of p53 with inactive p-Ser 9 GSK3b was responsible for suppressing p53 transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

“…Although it was considered effective in the treatment of inflammatory or autoimmune disorders by the inhibition of cytokine production Chen et al, 2000;Cibere et al, 2003), triptolide also has an antiproliferative effect for tumor cells in vitro and in vivo (Chang et al, 2001;Jiang et al, 2001;Yang et al, 2003;Fidler et al, 2003;Miyata et al, 2005;Carter et al, 2006;Wan et al, 2006). Among several intracellular pathways suggested to be responsible for the antiproliferative effect of triptolide, the suppression of p21 is one of the most convincing mechanisms (Chang et al, 2001;Fidler et al, 2003) but the details have never been elucidated. In this study, we demonstrated the effectiveness of triptolide to enhance CDDPinduced cytotoxicity via the modulation of p53 transcriptional activity in a cancer-specific manner, and clarified that p53 transcriptional activity was modulated through an intranuclear association of functional p53 with glycogen synthase kinase-3b (GSK3b) phosphorylated at serine 9 by protein kinase C (PKC), which suppressed p21 expression and evoked the JNKmitochondria apoptotic pathway.…”

Section: Introductionmentioning

confidence: 99%

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Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

et al. 2008

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To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3b (GSK3b), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3b axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

et al. 2008

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“…f., could enhance the apoptosis indirectly [12,13]. For example, triptolide increased doxorubicin-induced apoptosis of tumor cells through blocking p53-dependent p21 transcription [13].…”

Section: Discussionmentioning

confidence: 99%

“…f., which shows anti-inflammatory, immunosuppressive, antifertility and antitumor activities [9][10][11]. Recently, some experiments have shown that a derivative of TC, triptolide, can block p21-mediated growth arrest and then enhance chemotherapy-induced apoptosis in tumor cells, or cooperate with tumor necrosis factor-a to induce apoptosis in tumor cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

Induction of mitochondrion-mediated apoptosis of CHO cells by tripchloro- lide

Ren

Xiong

2003

Cell Res

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Tripchlorolide (TC) is a potent antitumor reagent purified from a Chinese herb Tripterygium Wilfordii Hook. f.. However, its cellular effects and mechanism of action are unknown. We showed here that TC induced apoptosis of Chinese Hamster Ovary (CHO) cells in time-and dose-dependent manners. TC resulted in the degradation of Bcl-2, the translocation of Bax from the cytosol to mitochondria, and the release of cytochrome c from mitochondria. Stable overexpression of human Bcl-2 could reduce the apoptosis of TC-treated cells by blocking the translocation of Bax and the release of cytochrome c. These results indicate that TC induces apoptosis of CHO cell by activating the mitochondrion-mediated apoptotic pathway involving the proteins of Bcl-2 family and cytochrome c.

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Triptolide Suppresses Alkali Burn‐Induced Corneal Angiogenesis Along with a Downregulation of VEGFA and VEGFC Expression

Geng

et al. 2017

The Anatomical Record

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Triptolide (TPL) is an active compound extracted from a Chinese herbal medicine tripterygium wilfordii Hook. f. (Celastraceae), which has been used as an anti-inflammatory drug for years. It also inhibits the growth and proliferation of different types of cancer cells. The inhibitory effect of TPL on angiogenesis after chemical-induced corneal inflammation was studied in vivo. The effects of TPL on the proliferation, apoptosis, migration, and tube formation of rat aortic endothelial cells (RAECs) were studied in vitro. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. Migration was analyzed using the scratch wound healing assay and transwell assay. Tube formation assay was used to examine angiogenesis. Real-time PCR and Western blot were used to determine the expression of vascular endothelial growth factor A (VEGFA) and VEGFC. To study the in vivo effects of TPL, the mouse model of alkali burn-induced corneal angiogenesis was used. The angiogenesis was analyzed by determining the density of the newly generated blood vessels in corneas. We found that TPL induced apoptosis and inhibited the proliferation of RAECs in a dose-dependent manner. TPL inhibited migration and tube formation of RAECs and decreased the expression of VEGFA and VEGFC in vitro. Furthermore, TPL suppressed alkali burn-induced corneal angiogenesis and inhibited the expression of VEGFA and VEGFC in corneas in vivo. In conclusion, topical TPL as a pharmacological agent has the ability to reduce angiogenesis in cornea and may have clinical indications for the treatment of corneal angiogenesis diseases which have to be further explored. Anat Rec, 300:1348-1355, 2017. © 2017 Wiley Periodicals, Inc.

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Triptolide and Chemotherapy Cooperate in Tumor Cell Apoptosis

Cited by 156 publications

References 24 publications

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

Induction of mitochondrion-mediated apoptosis of CHO cells by tripchloro- lide

Triptolide Suppresses Alkali Burn‐Induced Corneal Angiogenesis Along with a Downregulation of VEGFA and VEGFC Expression

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