Triptonide induces apoptosis and inhibits the proliferation of ovarian cancer cells by activating the p38/p53 pathway and autophagy.
Bioorganic & medicinal chemistry
Ovarian cancer is a common malignant tumor in women, and 70 % of ovarian cancer patients are diagnosed at an advanced stage. Drug chemotherapy is an important method for treating ovarian cancer, but recurrence and chemotherapy resistance often lead to treatment failure. In this study, we screened 10 extracts of Tripterygium wilfordii, a traditional Chinese herb, and found that triptonide had potent anti-ovarian cancer activity and an IC50 of only 3.803 nM against A2780 cell lines. In addition, we determined that triptonide had a better antitumor effect on A2780 cell lines than platinum chemotherapeutic agents in vitro and that triptonide had no significant side effects in vivo. We found that triptonide induced apoptosis in ovarian cancer cells through activation of the p38/p53 pathway and it also induced cell cycle arrest at the S phase. In addition, we demonstrated that triptonide could activate lethal autophagy, which led to growth inhibition and cell death in ovarian cancer cells, resulting in an anti-ovarian cancer effect. Triptonide exerts its anti-ovarian cancer effect through activation of the p38/p53 pathway and induction of autophagy to promote apoptosis, which provides a new candidate drug and strategy for the treatment of ovarian cancer.
10.1016/j.bmc.2024.117788
The lipogenic LXR-SREBF1 signaling pathway controls cancer cell DNA repair and apoptosis and is a vulnerable point of malignant tumors for cancer therapy.
Cell death and differentiation
Cancer cells are defective in DNA repair, so they experience increased DNA strand breaks, genome instability, gene mutagenesis, and tumorigenicity; however, multiple classic DNA repair genes and pathways are strongly activated in malignant tumor cells to compensate for the DNA repair deficiency and gain an apoptosis resistance. The mechanisms underlying this phenomenon in cancer are unclear. We speculate that a key DNA repair gene or signaling pathway in cancer has not yet been recognized. Here, we show that the lipogenic liver X receptor (LXR)-sterol response element binding factor-1 (SREBF1) axis controls the transcription of a key DNA repair gene polynucleotide kinase/phosphatase (PNKP), thereby governing cancer cell DNA repair and apoptosis. Notably, the PNKP levels were significantly reduced in 95% of human pancreatic cancer (PC) patients, particularly deep reduction for sixfold in all of the advanced-stage PC cases. PNKP is also deficient in three other types of cancer that we examined. In addition, the expression of LXRs and SREBF1 was significantly reduced in the tumor tissues from human PC patients compared with the adjacent normal tissues. The newly identified LXR-SREBF1-PNKP signaling pathway is deficient in PC, and the defect in the pathway contributes to the DNA repair deficiency in the cancer. Strikingly, further diminution of the vulnerable LXR-SREBF1-PNKP signaling pathway using a small molecule triptonide, a new LXR antagonist identified in this investigation, at a concentration of 8 nM robustly activated tumor-suppressor p53 and readily elevated cancer cell DNA strand breaks over an apoptotic threshold, and selectively induced PC cell apoptosis, resulting in almost complete elimination of tumors in xenograft mice without obvious complications. Our findings provide new insight into DNA repair and apoptosis in cancer, and offer a new platform for developing novel anticancer therapeutics.
10.1038/s41418-020-0514-3
Intravenous Administration of Triptonide Attenuates CFA-Induced Pain Hypersensitivity by Inhibiting DRG AKT Signaling Pathway in Mice.
Ling Yue-Juan,Ding Ting-Yu,Dong Fu-Lu,Gao Yong-Jing,Jiang Bao-Chun
Journal of pain research
Background:Currently, medical treatment of inflammatory pain is limited by a lack of safe and effective therapies. Triptonide (TPN), a major component of . with low toxicity, has been shown to have good anti-inflammatory and neuroprotective effects. The present study aims to investigate the effects of TPN on chronic inflammatory pain. Materials and Methods:Inflammatory pain was induced by intraplantar injection of complete Freund's adjuvant (CFA). TPN's three different doses were intravenously administered to compare the analgesic efficacy: 0.1 mg/kg, 0.5 mg/kg, and 2.0 mg/kg. The foot swelling was quantitated by measuring paw volume. Mechanical allodynia and thermal hyperalgesia were assessed with von Frey filament testing and Hargreaves' test, respectively. Western blots, qRT-PCR and immunofluorescence tests were used to analyze the expression of pAKT, (), (), and (). Two AKT inhibitors, AKT inhibitor Ⅳ and MK-2206, were used to examine AKT's effects on pain behavior and cytokines expression. Results:Intravenous treatment with TPN attenuated CFA-induced paw edema, mechanical allodynia, and thermal hyperalgesia. Western blotting and immunofluorescence results showed that CFA induced AKT activation in the dorsal root ganglion (DRG) neurons. However, these effects were suppressed by treatment with TPN. Furthermore, TPN treatment inhibited CFA-induced increase of pro-inflammatory cytokines, including , , and . Consistent with the in vivo data, TPN inhibited LPS-induced Akt phosphorylation and inflammatory mediator production in ND7/23 cells. Finally, intrathecal treatment with AKT inhibitor Ⅳ or MK-2206, attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, and simultaneously decreased the mRNA expression of , , and in DRG. Conclusion:These data indicate that TPN attenuates CFA-induced pain potentially via inhibiting AKT-mediated pro-inflammatory cytokines production in DRG. TPN may be used for the treatment of chronic inflammatory pain.
10.2147/JPR.S275320
Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells.
Cancer management and research
BACKGROUND:Osteosarcoma (OS) is the most common primary malignancy arise from bone and is one of the causes of cancer-related deaths. Triptonide (TN), a diterpenoid epoxide presented in , is shown to possess a broad spectrum of biological properties. METHODS:In this study, we investigate the growth inhibitory effect of TN against human OS cells and its underlying molecular mechanism of action. RESULTS:Findings of our in vitro study revealed that TN exhibited a dose-dependent cytotoxic effect in MG63 and U-2OS cells. ROS-mediated cytotoxic effect was achieved in OS cells treated with TN which was reversed upon NAC treatment. Significantly, increased expression of PERK, p-EIF2, GRP78, ATF4 and CHOP in TN-treated OS cells unfolds the molecular mechanism of TN targets ER stress-mediated apoptosis. Modulation of ERK MAPK pathway was also observed as evidenced by the increased phosphorylation of ERK (p-ERK) and p-p38 in TN-treated OS cells. CONCLUSION:Altogether, the outcome of the study for the first time revealed that TN exhibited its potential chemotherapeutic effects through ROS-mediated ER stress-induced apoptosis via p38 and ERK MAPK signaling pathways.
10.2147/CMAR.S258203
Identification of triptonide as a therapeutic agent for triple negative breast cancer treatment.
Gao Bowen,Chen Jiongyu,Han Bingchen,Zhang Xinfeng,Hao Jijun,Giuliano Armando E,Cui Yukun,Cui Xiaojiang
Scientific reports
Triple-negative breast cancer (TNBC) is associated with a high rate of early recurrence and distant metastasis, frequent development of therapeutic resistance, and a poor prognosis. There is a lack of targeted therapies for this aggressive subtype of breast cancer. Identifying novel effective treatment modalities for TNBC remains an urgent and unmet clinical need. In this study, we investigated the anti-cancer effect of triptonide, a natural compound derived from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, in TNBC. We found that triptonide inhibits human TNBC cell growth in vitro and growth of TNBC xenograft mammary tumors. It induces apoptosis and suppresses stem-like properties as indicated by reduced mammosphere formation and aldehyde dehydrogenase activity in TNBC cells. We show that triptonide downregulates multiple cancer stem cell-associated genes but upregulates SNAI1 gene expression. In support of SNAI1 induction as a negative feedback response to triptonide treatment, in vitro-derived triptonide-resistant HCC1806 cells display a markedly higher expression of SNAI1 compared with parental cells. Mechanistically, the increase of SNAI1 expression is mediated by the activation of JNK signaling, but not by ERK and AKT, two well-established SNAI1 regulators. Furthermore, knockdown of SNAI1 in the triptonide-resistant HCC1806 cells increases sensitivity to triptonide and reduces mammosphere formation. These results indicate that triptonide holds promise as a novel anti-tumor agent for TNBC treatment. Our study also reveals a SNAI1-associated feedback mechanism which may lead to acquired resistance to triptonide.
10.1038/s41598-021-82128-0
Triptonide effectively suppresses gastric tumor growth and metastasis through inhibition of the oncogenic Notch1 and NF-κB signaling pathways.
Xiang Shufen,Zhao Zhe,Zhang Tong,Zhang Bin,Meng Mei,Cao Zhifei,Zhou Quansheng
Toxicology and applied pharmacology
Gastric cancer ranks as the third leading cause of cancer-related death worldwide. The uncontrolled tumor growth and robust metastasis are key factors to cause the cancer patient death. Mechanistically, aberrant activation of Notch and NF-κB signaling pathways plays pivotal roles in the initiation and metastasis of gastric cancer. Despite great efforts have been made in recent decades, the effective drug against the advanced and metastatic gastric cancer is still lacking in the clinical setting. In this study, we found that triptonide, a small molecule (MW358) purified from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, effectively suppressed tumor growth and metastasis in xenograft mice without obvious toxicity at the doses we tested, resulting in potent anti-gastric cancer effect with low toxicity. Triptonide markedly inhibited human metastatic gastric cancer cell migration, invasion, proliferation, and tumorigenicity. Molecular mechanistic studies revealed that triptonide significantly reduced Notch1 protein levels in metastatic gastric cancer cells through degrading the oncogenic protein Notch1 via the ubiquitin-proteasome pathway. Consequently, the levels of Notch1 downstream proteins RBPJ, IKKα, IKKβ were significantly diminished, and nuclear factor-kappa B (NF-κB) phosphorylation was significantly reduced. Together, triptonide effectively suppresses gastric cancer growth and metastasis via inhibition of the oncogenic Notch1 and NF-κB signaling pathways. Our findings provide a new strategy and drug candidate for treatment of the advanced and metastatic gastric cancer.
10.1016/j.taap.2019.114870
TPL Inhibits the Invasion and Migration of Drug-Resistant Ovarian Cancer by Targeting the PI3K/AKT/NF-κB-Signaling Pathway to Inhibit the Polarization of M2 TAMs.
Le Fuyin,Yang Lilan,Han Yiwen,Zhong Yanying,Zhan Fuliang,Feng Ying,Hu Hui,Chen Tingtao,Tan Buzhen
Frontiers in oncology
Chemoresistance is the primary reason for the poor prognosis of patients with ovarian cancer, and the search for a novel drug treatment or adjuvant chemotherapy drug is an urgent need. The tumor microenvironment plays key role in the incidence and development of tumors. As one of the most important components of the tumor microenvironment, M2 tumor-associated macrophages are closely related to tumor migration, invasion, immunosuppressive phenotype and drug resistance. Many studies have confirmed that triptolide (TPL), one of the principal components of , possesses broad-spectrum anti-tumor activity. The aims of this study were to determine whether TPL could inhibit the migration and invasion of A2780/DDP cells and by inhibiting the polarization of M2 tumor-associated macrophages (TAMs); to explore the mechanism(s) underlying TPL effects; and to investigate the influence of TPL on murine intestinal symbiotic microbiota. results showed that M2 macrophage supernatant slightly promoted the proliferation, invasion, and migration of A2780/DDP cells, which was reversed by TPL in a dose-dependent manner. Animal experiments showed that TPL, particularly TPL + cisplatin (DDP), significantly reduced the tumor burden, prolonged the life span of mice by inhibiting M2 macrophage polarization, and downregulated the levels of CD31 and CD206 (CD31 is the vascular marker and CD206 is the macrophage marker), the mechanism of which may be related to the inhibition of the PI3K/Akt/NF-κB signaling pathway. High-throughput sequencing results of the intestinal microbiota in nude mice illustrated that and were upregulated by DDP and TPL respective. We also found that and were downregulated by DDP combined with TPL. Our results highlight the importance of M2 TAMs in Epithelial Ovarian Cancer (EOC) migration ability, invasiveness, and resistance to DDP. We also preliminarily explored the mechanism governing the reversal of the polarization of M2 macrophages by TPL.
10.3389/fonc.2021.704001
Morinda officinalis How. - A comprehensive review of traditional uses, phytochemistry and pharmacology.
Zhang Jian-Hua,Xin Hai-Liang,Xu Yue-Ming,Shen Yi,He Yu-Qiong,Hsien-Yeh ,Lin Bing,Song Hong-Tao,Juan-Liu ,Yang Hai-Yue,Qin Lu-Ping,Zhang Qiao-Yan,Du Juan
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:The medicinal plant Morinda officinalisHow. (MO) and its root have long been used in traditional medicines in China and northeast Asia as tonics for nourishing the kidney, strengthening the bone and enhancing immunofunction in the treatment of impotence, osteoporosis, depression and inflammatory diseases such as rheumatoid arthritis and dermatitis. AIM OF THE REVIEW:This review aims to sum up updated and comprehensive information about traditional usage, phytochemistry, pharmacology and toxicology of MO and provide insights into potential opportunities for future research and development of this plant. METHODS:A bibliographic investigation was performed by analyzing the information available on MO in the internationally accepted scientific databases including Pubmed, Scopus and Web of Science, SciFinder, Google Scholar, Yahoo, Ph.D. and M.Sc. dissertations in Chinese. Information was also obtained from some local and foreign books on ethnobotany and ethnomedicines. RESULTS:The literature supported the ethnomedicinal uses of MO as recorded in China for various purposes. The ethnomedical uses of MO have been recorded in many regions of China. More than 100 chemical compounds have been isolated from this plant, and the major constituents have been found to be polysaccharides, oligosaccharides, anthraquinones and iridoid glycosides. Crude extracts and pure compounds of this plant are used as effective agents in the treatment of depression, osteoporosis, fatigue, rheumatoid arthritis, and infertility due to their anti-depressant, anti-osteoporosis, pro-fertility, anti-radiation, anti-Alzheimer disease, anti-rheumatoid, anti-fatigue, anti-aging, cardiovascularprotective, anti-oxidation, immune-regulatory, and anti-inflammatory activities. Pharmacokinetic studies have demonstrated that the main components of MO including monotropein and deacetyl asperulosidic acid are distributed in various organs and tissues. The investigation on acute toxicity and genotoxicity indicated that MO is nontoxic. There have no reports on significant adverse effect at a normal dose in clinical application, but MO at dose of more than 1000mg/kg may cause irritability, insomnia and unpleasant sensations in individual cases. CONCLUSION:MO has emerged as a good source of traditional medicines. Some uses of this plant in traditional medicines have been validated by pharmacological investigations. However, the molecular mechanism, structure-activity relationship, and potential synergistic and antagonistic effects of its multi-components such as polysaccharides, oligosaccharides, anthraquinones and iridoid glycosides need to be further elucidated, and the structural feature of polysaccharides also need to be further clarified. Sophisticated analytical technologies should be developed to comprehensively evaluate the quality of MO based on HPLC-fingerprint and content determination of the active constituents, knowing that these investigations will help further utilize this plant.
10.1016/j.jep.2017.10.028
Triptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms.
Zhou Zhao-Li,Yang Ya-Xi,Ding Jian,Li Yuan-Chao,Miao Ze-Hong
Natural product reports
Triptolide, a principal bioactive ingredient of Tripterygium wilfordii Hook F, has attracted extensive exploration due to its unique structure of a diterpenoid triepoxide and multiple biological activities. This review will focus on the structural modifications, structure-activity relationships, pharmacology, and clinical development of triptolide in the last forty years.
10.1039/c2np00088a
Triptolide-targeted delivery methods.
Xu Hongtao,Liu Bo
European journal of medicinal chemistry
Triptolide, a complex triepoxide diterpene natural product, has attracted considerable interest in the medicinal society due to its multiple biological activities. However, poor water solubility, narrow therapeutic window and multi-organ toxicity have greatly hindered its clinical application. In order to improve its clinical potential, either structural modification or the development of novel targeted delivery systems for triptolide have been executed worldwide in the past decades. In this review, we systematically summarized strategies that have been utilized to develop triptolide-targeted delivery methods, including direct conjugation of triptolide to selected ligands such as sugar, short peptide, oligonucleotide, antibody and most importantly encapsulation of triptolide with well-designed nano-vehicle. Thanks to the potent multiple biological activities of triptolide, either direct conjugation of triptolide to selected ligands or encapsulation of triptolide with nanocarriers could provide better anti-inflammatory or anticancer activity. Thus, these targeted delivery strategies could be taken as a starting point for future utilization of triptolide and also other NPs in experimental clinical therapy.
10.1016/j.ejmech.2018.12.058
Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins.
Zhang Mengli,Meng Mei,Liu Yuxi,Qi Jindan,Zhao Zhe,Qiao Yingnan,Hu Yanxing,Lu Wei,Zhou Zhou,Xu Peng,Zhou Quansheng
Breast cancer research : BCR
BACKGROUND:Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic. METHODS:We used TNBC cells and xenografted mice as models to explore triptonide-mediated inhibition of TNBC metastasis and tumor growth. Colony formation assay was used to quantify the tumorigenesis of TNBC cells. Wound-healing and cell trans-well assays were utilized to measure cell migration and invasion. Tube formation assay was applied to access tumor cell-mediated vasculogenic mimicry. Western blot, quantitative-PCR, immunofluorescence imaging, and immunohistochemical staining were used to measure the expression levels of various tumorigenic genes in TNBC cells. RESULTS:Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2). CONCLUSIONS:Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.
10.1186/s13058-021-01488-7
Triptonide Inhibits the Cervical Cancer Cell Growth via Downregulating the RTKs and Inactivating the Akt-mTOR Pathway.
Oxidative medicine and cellular longevity
The high incidence and mortality of cervical cancer (CC) require an urgent need for exploring novel valuable therapeutics. Triptonide (TN) is a small molecule monomer extracted from the Chinese herb . Our results showed that TN, at only nanomolar concentrations, strongly inhibited growth, colony formation, proliferation, migration, and invasion of established and primary human cervical cancer cells. TN induced apoptosis and cell cycle arrest in cervical cancer cells. Moreover, cervical cancer cell migration and invasion were suppressed by TN. It was however noncytotoxic and proapoptotic to normal cervical epithelial cells and human skin fibroblast cells. Gene set enrichment analysis (GSEA) of RNA sequencing data of differentially expressed genes (DEGs) in TN-treated cervical cancer cells implied that DEGs were enriched in the receptor tyrosine kinase (RTK) signaling and PI3K-Akt-mTOR cascade. In cervical cancer cells, RTKs, including EGFR and PDGFR, were significantly downregulated and Akt-mTOR activation was largely inhibited after TN treatment. , oral administration of TN significantly inhibited subcutaneous cervical cancer xenograft growth in nude mice. EGFR and PDGFR downregulation as well as Akt-mTOR inactivation was detected in TN-treated HeLa xenograft tumor tissues. Thus, TN inhibits human cervical cancer cell growth and . Its anticervical cancer activity was associated with RTK downregulation and Akt-mTOR inactivation.
10.1155/2022/8550817
Antitumor mechanisms and future clinical applications of the natural product triptolide.
Cancer cell international
Triptolide (TPL) is a compound sourced from Tripterygium wilfordii Hook. F., a traditional Chinese medicinal herb recognized for its impressive anti-inflammatory, anti-angiogenic, immunosuppressive, and antitumor qualities. Notwithstanding its favorable attributes, the precise mechanism through which TPL influences tumor cells remains enigmatic. Its toxicity and limited water solubility significantly impede the clinical application of TPL. We offer a comprehensive overview of recent research endeavors aimed at unraveling the antitumor mechanism of TPL in this review. Additionally, we briefly discuss current strategies to effectively manage the challenges associated with TPL in future clinical applications. By compiling this information, we aim to enhance the understanding of the underlying mechanisms involved in TPL and identify potential avenues for further advancement in antitumor therapy.
10.1186/s12935-024-03336-y
The Promising Therapeutic Potential of Celastrol for Fibrotic Diseases: A Systematic Literature Review on Its Mechanism.
Cureus
Celastrol is a pentacyclic tripterine sourced from hook root. Celastrol can exert certain biological functions such as antitumor, anti-inflammatory, and antiproliferative properties. Celastrol was shown from the previous literature to be capable of attenuating many fibrotic diseases. As the effects of various fibrotic diseases such as atherosclerosis, cancer, and ischemia affect more people with devastating repercussions, this warrants celastrol to be exploited as a phytotherapeutic drug. The purpose of this study is to review previous research and identify the proposed therapeutic mechanisms of celastrol in fibrotic diseases focusing on both the and experimental models. A systematic literature search on Web of Science (WoS), Scopus, and ScienceDirect that included articles published between 2012 and 2022 was carried out using the keywords "celastrol", "tripterine", "fibrotic disease", and "fibrosis". After screening the initial search yield of 405 articles, 25 articles were included in this review. The study findings summarize the potential therapeutic mechanism of celastrol in the attenuation of fibrotic diseases in and experimental models. It shows that celastrol is useful as a treatment means. However, more studies are needed on the effects of celastrol on humans to carry out clinical trials to verify the long-term benefits of celastrol.
10.7759/cureus.44269
Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer.
Acta pharmacologica Sinica
Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.
10.1038/s41401-023-01219-y
Triptolide: reflections on two decades of research and prospects for the future.
Tong Lu,Zhao Qunfei,Datan Emmanuel,Lin Guo-Qiang,Minn Il,Pomper Martin G,Yu Biao,Romo Daniel,He Qing-Li,Liu Jun O
Natural product reports
Covering: 2000 to 2020 Triptolide is a bioactive diterpene triepoxide isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal plant whose extracts have been used as anti-inflammatory and immunosuppressive remedies for centuries. Although triptolide and its analogs exhibit potent bioactivities against various cancers, and inflammatory and autoimmune diseases, none of them has been approved to be used in the clinic. This review highlights advances in material sourcing, molecular mechanisms, clinical progress and new drug design strategies for triptolide over the past two decades, along with some prospects for the future course of development of triptolide.
10.1039/d0np00054j
Inhibiting NF-κB-S100A11 signaling and targeting S100A11 for anticancer effects of demethylzeylasteral in human colon cancer.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Colon cancer is a common and deadly malignancy of the gastrointestinal tract. Targeting proteins that inhibit tumor proliferation could lead to innovative treatment strategies for this disease. Demethylzeylasteral, extracted naturally from Tripterygium wilfordii Hook. f., demonstrates incredible anti-colon cancer activity. However, the molecular mechanism behind this requires further investigation. This study aims to identify crucial targets and mechanisms of demethylzeylasteral in treating colon cancer, making it a promising candidate for anti-tumor therapy. Through gene knockout, overexpression techniques, and double Luciferase experiments, we confirmed that demethylzeylasteral reduces S100A11 expression in HT29 cells and in vivo tumor models to anti-colon cancer. By conducting Surface Plasmon Resonance, immunofluorescence staining, and confocal laser microscopy observations, we verified the direct interaction between demethylzeylasteral and S100A11, and explored the impact of S100A11's subcellular localization on cell proliferation. Demethylzeylasteral inhibited S100A11 expression and exhibited anti-cancer activity in both in vitro and in vivo colon cancer models. Conversely, overexpression of S100A11 hindered apoptosis induced by demethylzeylasteral. Additionally, we found that knockdown or overexpression of NF-κB respectively decreased or increased S100A11 expression, subsequently affecting cell proliferation. The dual Luciferase reporting experiment revealed that NF-κB is an upstream transcription factor regulating S100A11 expression. And Surface plasmon resonance confirmed that S100A11 can directly interact with demethylzeylasteral, this interaction limited the transport of S100A11 from the cytoplasm to nucleus, attenuation S100A11 mediated cell proliferation effect.
10.1016/j.biopha.2023.115725
A comprehensive review on celastrol, triptolide and triptonide: Insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Celastrol, triptolide and triptonide are the most significant active ingredients of Tripterygium wilfordii Hook F (TWHF). In 2007, the 'Cell' journal ranked celastrol, triptolide, artemisinin, capsaicin and curcumin as the five natural drugs that can be developed into modern medicinal compounds. In this review, we collected relevant data from the Web of Science, PubMed and China Knowledge Resource Integrated databases. Some information was also acquired from government reports and conference papers. Celastrol, triptolide and triptonide have potent pharmacological activity and evident anti-cancer, anti-tumor, anti-obesity and anti-diabetes effects. Because these compounds have demonstrated unique therapeutic potential for acute and chronic inflammation, brain injury, vascular diseases, immune diseases, renal system diseases, bone diseases and cardiac diseases, they can be used as effective drugs in clinical practice in the future. However, celastrol, triptolide and triptonide have certain toxic effects on the liver, kidney, cholangiocyte heart, ear and reproductive system. These shortcomings limit their clinical application. Suitable combination therapy, new dosage forms and new routes of administration can effectively reduce toxicity and increase the effect. In recent years, the development of different targeted drug delivery formulations and administration routes of celastrol and triptolide to overcome their toxic effects and maximise their efficacy has become a major focus of research. However, in-depth investigation is required to elucidate the mechanisms of action of celastrol, triptolide and triptonide, and more clinical trials are required to assess the safety and clinical value of these compounds.
10.1016/j.biopha.2023.114705