|
 
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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 14
| Issue : 9 | Page : 271-275 |
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Triptolide: A new star for treating human malignancies
Ping Yan1, Xiaotian Sun2
1 Department of Internal Medicine, University Hospital, Qufu Normal University, Qufu, China
2 Department of Internal Medicine, Clinic of August First Film Studio, Beijing, China
| Date of Web Publication | 29-Jun-2018 |
Correspondence Address:
Xiaotian Sun
No. 1, North Liuliqiao, Beijing 100161
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0973-1482.235340
In recent years, cancer has become the most common human disease worldwide, and great attentions have been paid to clarifying the carcinogenesis and identifying new effective antitumor therapy. Although great progress has been made in this research field, human malignant diseases could still not be radically cured. Thunder god vine is a herbal medicine, which has proved to exert efficient antitumor activity in various human cancers such as lung cancer, pancreatic cancer, and colon cancer. In vivo and in vitro experiments showed that thunder god vine extract triptolide could inhibit tumor cell proliferation, cell migration, and cell invasion. Here, we overviewed the functional role of triptolide in human malignancies and its promising therapeutic potential in treating such deadly diseases.
Keywords: Cancer, Chinese herb, therapy, thunder god vine, triptolide
How to cite this article:
Yan P, Sun X. Triptolide: A new star for treating human malignancies. J Can Res Ther 2018;14, Suppl S2:271-5 |
| > Introduction | |  |
Chinese traditional medicine has been introduced to the treatment of various human diseases for a long time.[1] The potential molecular mechanism is associated with the specific functions of certain bioactive components in these herbs.[2] Currently, many kinds of Chinese herbs have attracted great attentions from researchers worldwide, which are considered to be promising therapeutic candidates for inflammatory diseases and cancer.[3]
As the lifestyle changes, the incidence of cancer is on the increase year by year.[4],[5],[6] Currently, the main treatments for cancer include surgery, chemotherapy, radiotherapy, target therapy, and their combinational therapy. However, there are still a large proportion of patients diagnosed at advanced stage, who have lost the chance for radical therapy, and only a small part of patients at early stage will have good therapeutic efficacy because of the high recurrence rate. Generally, the survival rate for cancer patients remains very low due to lack of effective treatment, and it is still a challenge to find a cure for human cancers.[7] Many Chinese herbs could help suppress tumor growth probably by modulating the immune functions and microenvironment such as Qingyihuaji, Taxus cuspidate, and Pulsatilla chinensis.[8] Among them, thunder god vine, also called lei gong teng, is widely acknowledged to possess anti-inflammatory and antitumor activities, and triptolide is the bioactive molecule extracted.[9],[10] Thus, we overview the recent literature on triptolide therapy for multiple human cancers and further summarized the related molecular mechanisms. Our paper could help deepen the insight on the role of triptolide as an antitumor agent in treating such devastating diseases and improving patients' outcome.
| > Antitumor Molecular Mechanisms of Triptolide | | |
A complex of genetic and environmental factors participates in the development and progression of human cancers.[11],[12]In vitro and in vivo experiments demonstrated that triptolide could inhibit tumor cell proliferation, cell invasion, and migration, decrease tumor vascularization but induce cell apoptosis [Figure 1]. Triptolide can also function by interacting with many other regulators such as microRNAs (miRNAs) (i.e., miR-21, miR-204, and miR-142-3p). | Figure 1: Triptolide serves as a new therapeutic agent for treating multiple human cancers by modulating multiple signaling pathways, which participate in the regulation of cell proliferation, cell apoptosis, angiogenesis, cell migration, and invasion of tumor cells
Click here to view |
Cell proliferation inhibition
Uncontrolled cell proliferation is one of the main features in tumor. Li et al. have ever found that the treatment of triptolide could greatly reduce the cell proliferation of human nonsmall cell lung cancer PC-9 cells.[13] Herb-derived compound triptolide can inhibit cell proliferation in chemoresistant pancreatic cancer cells in vitro, and the anticancer efficacy was even superior to that by gemcitabine.[14] The inhibitory effect of triptolide on tumor cells was independent of p53 status in breast cancer, and triptolide also enhanced the cytotoxic activity of doxorubicin.[15] Triptolide micelles inhibited the cell proliferation rate of ovarian cancer SKOV3 cells in a time- and dose-dependent manner, which was enhanced after 48 h and 72 h treatment compared to triptolide.[16] Cell cycle analysis revealed that triptolide and triptolide micelles decreased cell proliferation by causing G2/M arrest. Cell growth in human endometrial cancer HEC-1B cells was observed by an inverted phase contrast microscope, which was significantly inhibited by triptolide. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that the inhibition of triptolide on HEC-1B cell proliferation was also in a dose- and time-dependent manner. High-dose triptolide possessed a comparable tumor-inhibitory action with cisplatin (−50%), and high-dose triptolide significantly inhibited Bcl-2. and vascular endothelial growth factor (VEGF) expression in the endometrial cancer xenograft model by comparing with that treated by normal saline control (P < 0.05).[17]
Cell apoptosis induction
Triptolide could sensitize the tumor cells to cell apoptosis.[18],[19] The triptolide-induced sensitization in human renal carcinoma cells and pancreatic cancer enhanced tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptotic death by increasing TRAIL-R2 (DR5) and decreasing heat shock protein (HSP) 70 expression.[20],[21] Treatment with triptolide increased cell apoptosis in lung cancer by enhancing caspase-3 and -9 activity.[13] Similar effect of increased cell apoptosis under triptolide was also found in breast cancer, pancreatic cancer, liver cancer, ovarian cancer, neuroblastoma, and colon cancer.[10],[15],[16],[22],[23],[24] Although triptolide induced a significant increased cell apoptosis in ovarian cancer by inducing caspase-dependent way and inhibiting nuclear factor kappa B (NF-κB) signaling.[16] Triptolide induced nasopharyngeal cancer HNE1/DDP cell apoptosis via inducing reactive oxygen species (ROS) generation, which was abolished by ROS inhibitor N-acetyl-L-cysteine. Western blot also showed that triptolide alone or in combination with cisplatin could increase Bax and caspase-9 expression but reduce Bcl-2 and Mcl-1 expression.[25] Flow cytometry analysis showed that low concentration (5 ng/ml) of triptolide could induce S-phase arrest in HEC-1B cells, whereas higher concentration (40 or 80 ng/ml) induced G2/M phase arrest and cell apoptosis.[17] Triptolide induced cell morphological changes, cell apoptosis, and cytotoxic effects through G0/G1 phase arrest murine leukemia WEHI-3 cells by increasing ROS production, Ca 2+ release, and mitochondrial membrane potential and activating caspase-8, -9 and -3.[26] Triptolide increased protein levels of Fas, Fas-L, Bax, cytochrome c, caspase-9, Endo G, Apaf-1, PARP, and caspase-3 but reduced levels of AIF, ATF6α, ATF6 β, and GRP78 in WEHI-3 cells and triptolide can also stimulate the process of autophagy.[27] In addition, triptolide sensitized human breast cancer cells to TNF-α-induced apoptosis by inhibiting IκBα activation and downstream antiapoptotic genes of NF-κB activation, XIAP, and cIAP1/2, increasing cleaved PARP, and further activating caspase-3.[28] The dose- and time-dependent triptolide-induced ERK activation modulated the expression of the Bcl-2 protein family member Bax but did not affect the downregulation of Bcl-xL expression in breast cancer MDA-MB-231 cells. Upstream signals of ERK activation caused generation of ROS and endoplasmic reticulum stress predominantly via the PERK-eIF2α pathway, and ERK activation was critical in mediating triptolide-induced caspase-dependent cell apoptosis.[29],[30]
Suppressed cell invasion and migration
Triptolide significantly inhibited the migration and invasion of breast cancer B16F10 cells via downregulating NF-κB expression and inhibiting NF-κB DNA binding, which then suppressed matrix metalloproteinase (MMP)-2 and -9 level in a dose-dependent manner.[31] It was observed that triptolide markedly reduced CXCR4, SOS1, GRB2, p-ERK, FAK, p-AKT, Rho A, p-JNK, NF-κB, MMP-9, and MMP-2, but increased PI3K and p-p38 and COX2 in protein level. Triptolide inhibited the messenger RNA (mRNA) level of MMP-2, FAK, ROCK-1, and NF-κB but did not significantly affect TIMP-1 and -2 in B16F10 cells in vitro.[31] Triptolide decreased lung cancer cell migration and invasion in vitro and inhibited metastasis in mice model by deactivating focal adhesion kinase and regulating miRNAs involved in cellular movement, which caused deregulation in the migration-related signaling.[32] Conditional medium from triptolide-treated pancreatic cancer PANC-1 cells could inhibit cell proliferation, migration, and tube formation in human umbilical vein endothelial cells (HUVECs).[33] Triptolide potently inhibited cell growth and reduced basal and stimulated HCT116 migration in colon cancer HT29 and HCT116 cells by decreasing cytokines receptors such as thrombin receptor, CXCR4, TNF receptors, and transforming growth factor-β receptors which were potentially involved in cell migration and cancer metastasis.[34] In ovarian cancer, triptolide decreased the MMP-7 and MMP-19 promoter activity and cell migration in vitro and inhibited tumor formation and metastasis in nude mice model by downregulating MMP-7 and MMP-19 mRNA and protein expression but upregulating E-cadherin expression in a dose-dependent manner.[35]
Decreased tumor vascularization
Vascularization plays an important role in the progression of tumor. Tumor cells could release VEGF, which is a strong vascularization stimulator. VEGF, which is a direct target of hypoxia-inducible factor 1α (HIF-1α), was suppressed by reduced HIF-1α, which was downregulated by triptolide treatment in pancreatic cancer cells in a dose-dependent manner, and the microvessel density of tumor tissues was consequently reduced in a xenograft model of pancreatic cancer.[36] ChIP-on-chip and Western blot showed that H3K4me3 was highly enriched on c-Myc and VEGFA gene promoters and could upregulate their expression, whereas triptolide reduced c-Myc and VEGFA level in multiple myeloma KM3 cells by blocking the H3K4me3 accumulation on their promoters.[37] Triptolide significantly reduced tumor growth in pancreatic and colon cancer mouse xenografts, by inducing apoptosis, inhibiting angiogenesis, and reducing COX-2 and VEGF.[33],[34] Triptolide downregulated NF-κB pathway in HUVECs and impaired VEGF expression in thyroid carcinoma TA-K cells. Triptolide and conditioned medium from triptolide-treated TA-K cells significantly weakened cell proliferation, migration, and tube formation of HUVECs, and triptolide could inhibit TA-K cell-induced tumor growth, vascular formation, and VEGF expression. This inhibition of triptolide on tumor angiogenesis in thyroid cancer was associated with the dual action on vascular endothelial cells and tumor cells.[38]
Interactions with other functional regulators
Triptolide treatment reduced miR-21 expression and enhanced phosphatase and tensin homolog (PTEN) protein expression levels in the PC-9 cells. Furthermore, the upregulation of miR-21 expression levels suppressed the effect of triptolide on cell viability and PTEN protein expression levels in PC-9 cells.[13] Triptolide modulated miR-204 and miR-142-3p level in pancreatic cancer.[39],[40] A microarray analysis of gene expression showed that 11 genes, including c-Myc, SOX9, and Ets2, were downregulated at an early stage following triptolide treatment.[36] Triptolide induced DNA damage and inhibited DNA damage and repair-associated gene expression, which may partly explain triptolide-mediated inhibition on cell growth in vitro in human malignant melanoma A375.S2 cells and pancreatic cancer.[41],[42] O-GlcNAc modification of transcription factor Sp1 was also involved in triptolide's anticancer action.[43],[44],[45] Treatment with triptolide could disrupt the cytosolic complex of HSF1, p97, HSP90, and the histone deacetylase 6, leading to HSP90 acetylation and abrogation of its chaperone function and attenuating HSP90-dependent survival signaling in leukemia mice model.[46]
| > Therapeutic Potential of Triptolide in Treating Human Malignancies | | |
At recent, more and more Chinese herbs and their extracts have been clinically applied to the specific therapy for multiple cancers.[47],[48],[49] Triptolide alone or combined with other anticancer agents may enhance the anticancer therapeutic efficacy.[14],[50],[51] Triptolide and amino terminal fragment of urokinase could synergistically inhibit the tumor growth by inhibiting angiogenesis.[52] Minnelide, which is a prodrug of triptolide, has also been extensively investigated in basic and clinical research, and preclinical evaluation has validated its therapeutic potential in lung cancer, pancreatic cancer, and liver cancer.[53],[54],[55]In vivo, combination therapy of minnelide and agonistic anti-DR5 monoclonal antibody significantly decreased tumor burden and increased animal survival in mice bearing orthotopic renal carcinoma and in preclinical mice model of pancreatic cancer.[20],[56] Minnelide sensitized tumor cells to gemcitabine and pemetrexed, which was comparable with triptolide.[57] Minnelide also improved the antitumor action in human papillomavirus-positive head and neck squamous cell carcinoma, osteosarcoma, and epithelial ovarian cancer.[23],[58],[59] The side population in pancreatic cancer was also decreased by minnelide treatment.[60],[61] Taken together, minnelide might be a promising therapeutic agent in cancer treatment.
| > Conclusion | | |
Triptolide and its prodrug minnelide have a bright prospect in treating various kinds of human tumors including both solid and nonsolid cancers. These antitumor activities involve the regulation on tumor cell proliferation, apoptosis, invasion, and migration by modulating NF-κB and ERK signaling and the downstream gene expressions together with interacting with miRNAs and chaperones. The therapeutic potential has been preclinically evaluated, whereas their clinical application should be further investigated in future.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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