Triptolide: pharmacological activities and toxicity

Introduction

Triptolide (Figure 1), a diterpene triepoxide, is a major active component extracted from Chinese herbTripterygium wilfordii Hook F, which exhibits multiple pharmacological effects, including anti-inflammatory,anti-oxidant, immune modulation, neuroprotection,and anti-tumor activity. And triptolide has been widely used to treat autoimmune, inflammatory diseases and different types of tumors. The pharmacological effects of triptolide involve multiple signal pathways and several cellular targets have been demonstrated, such as Hsp70, nuclear factor-kappa B, vascular endothelial growth factor and RNA polymeraseⅡ. Recent studies have revealed that triptolide is capable of modulating autophagic pathway in several cell lines and tissues. [1]

Main pharmacological activities

Increasing experimental evidence has suggested that triptolide induces apoptosis, modulates autophagy, arrests cell cycle progression, inhibits angiogenesis, and triggers autophagy through several key molecular mechanisms by modulating signaling pathways involved in the regulation of endogenous reactive oxygen species (ROS) and nitric oxide (NO), Histone methyltransferase, HSP70, RNA polymerase I and II, Jak2, Mcl-1, Bcl-2/Bax , caspase 8, 9, and 3, PARP-1/2, NF-kB ,NFAT, XIAP, ber-abl, p53/p21(waf1/cip1), MAPK, PI3K, MPK1, ERK-1/2, JNK-1/2 and 5-LOX. These multiple pathway modulations support the viewpoint that the cross-talk network amongst these targets and signaling pathways are responsible for the multiple promising anticancer activities of triptolide both in vitro and in vivo. As it has been increasingly recognized that the treatment for challenging cancers with resistance may benefit more from a multi-pharmacological approach, which modulates a network of cancer related targets,rather than by “switching” on or off a single target, little wonder, thus, that triptolide should be an ideal multifunctional natural product that is capable of inhibiting proliferation and inducing apoptosis of cancer cells in a multitarget manner and worthy of future development as anticancer agent.[2]

Triptolide not only inhibits cancer cell proliferation and induces apoptosis, but also suppresses inflammation and stimulates cytoprotection by inhibiting of pro-inflammatory cytokine and chemokine, including PMA, THF-a, IFN-r , MCP-1, MIP-1a, MIP-1B, RANTES, TARC, IP-10, MCP-1, G-CSF, IL-1B, IL-6, IL-8, Cxcl-1, COX-2 and NO. These effects may associate with its anti-inflammatory activities related diseases, such as Parkinson's disease, Alzheimer's disease, kidney disease,chronic glaucoma and lung inflammation. Meanwhile,through regulation of immune-related cell and inflammatory mediators, triptolide showed potent immunosuppressive activity,thus it has the great potential for the treatment of immune diseasessuch as RA , psoriatic , SLE and allograft rejection.Recent studies have also shown that nanomolar concentrations of triptolide were shown to potently inhibit HIV-1 replication in vitroby specific prompting the degradation of the virally encoded Tatprotein.

Toxicity and Adverse Reactions

Despite the promising pharmacological activities of triptolide,the relativity narrow therapeutic window, poor water solubility (0.017 mg/ml, pH 7.4 at room temperature) [66], multi-organ toxicity as well as imprecise mechanisms of action have greatly hindered its clinical development. With the increasing clinical application of T. wilfordii and triptolide, increasing numbers of studies and clinical case reports indicate that triptolide has serious adverse effects. Currently, triptolide has a narrow therapeutic window and induces serious toxicity and side effects, which limits its clinical application.[3] It is well known that triptolide could cause hepatotoxicity, nephrotoxicity, cardiotoxicity, reproductive toxicity, and could also exert toxicity on other organs.

(1) Hepatotoxicity 

Liver injury is the most common adversereaction caused by triptolide, and has causedwidespread concern. Many studies have been carried out to explain the mechanism of triptolide-inducedliver toxicity, mainly focusing on commonphenomena such as oxidative stress and inflammation[4-5].In recent years, researchers have discovered that mitotic phagocytosis associated with mitochondrial fission may be a new mechanism of induced triptolide hepatotoxicity [6]

(2) Cardiotoxicity

Studies have shown that triptolide could cause acute myocardial damage, such as myocardium denaturation, swelling, cytolysis and necrosisc []. Research by Shurong Wang et al. showed thattriptolide caused an increase in the expression of morethan 108 microRNAs in the heart of male rats by more than twofold and reduced AhR levels in the myocardium and circulation, inducing acute cardiotoxicity [136]. Therefore, circulating AhR levelsand microRNA levels can be used as early warning biomarkers for triptolide-induced cardiotoxicity.

(3) Reproductive toxicity 

Triptolide has strong reproductive toxicity,mainly in males. Triptolide can inhibit spermatogenesis and testosterone marker enzymes,reduce sperm count, lower the gonadal index and destroy the testicular microstructure. Bo Ma etal. evaluated the mechanism of triptolide-induced reproductive toxicity and identified possible new biomarkers. They reported that triptolide-mediated down regulation of PPAR caused abnormal testicular lipid and energy metabolism,which led to sperm damage, revealing the mechanism of the reproductive toxicity induced by triptolide

Long-term administration of triptolide could also cause splenic and hepatic injury. Gastrointestinal tract symptoms, such as nausea, anorexia, diarrhoea and bleeding are also reported to be caused by adverse effects of triptolide.

In order to circumvent the above mentioned problems and find triptolide derivatives with good drug-like properties, extensive total synthesis and structure modification efforts have been executed in  the past few decades. Benitting from these works, an increasingly clear structure-activity relationships (SARs) of triptolide could be summarized . Furthermore, some derivatives such as (5R)-5-Hydroxytriptolide (LLDT-8) and Minn-elide have advanced in clinical trials for rheumatoid arthritis (RA), HIV associated chronic immune activation, and pancreatic cancer therapeutics, respectively.[2-3]

Conclusion

In the past decades, triptolide has attracted considerable interests in the organic and medicinal chemistry society owing toits intriguing structure and promising multiple pharmacological activities. However, its limited water solubility and oral bioavailability, imprecise mechanism of action and severe toxicity, scarce from natural source and difficulty in the synthesis have greatly hindered its clinical potential. Hence, to circumvent such problems,a lot of elegant total synthesis and/or semi-synthesis of triptolide have been developed. With the advancement of the total synthesis,various triptolide derivative have been synthesized and tested in the search for more drug-like derivatives for potential anticancer agents, anti-inflammatory agents, immunosuppressive agents andanti-Alzheimer's agents, etc. Meanwhile, through designing and synthesizing of various of bioactive probes, some molecular targets that are responsible for the multiple pharmacology activities as well as toxicity of triptolide have identified. It will no doubt be helpful for the future design of new drug-like triptolide derivatives.Nevertheless, to advance triptolide derivatives into viable clinical therapies, there remains to be several issues and new directions for future research in the area.[2]

References

[1] Wei YM, Wang YH, Xue HQ, Luan ZH, Liu BW, Ren JH. Triptolide, A Potential Autophagy Modulator. Chin J Integr Med. 2019;25(3):233-240.

[2] Hou W, Liu B, Xu H. Triptolide: Medicinal chemistry, chemical biology and clinical progress. Eur J Med Chem. 2019;176:378-392.

[3] Gao J, Zhang Y, Liu X, Wu X, Huang L, Gao W. Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives. Theranostics. 2021;11(15):7199-7221.

[4] Cao LJ, Hou ZY, Li HD, Zhang BK, Fang PF, Xiang DX, et al. The Ethanol Extract of Licorice (Glycyrrhiza uralensis) Protects against Triptolide-Induced Oxidative Stress through Activation of Nrf2. Evid Based Complement Alternat Med. 2017; 2017: 2752389.

[5] Fu Q, Huang X, Shu B, Xue M, Zhang P, Wang T, et al. Inhibition of mitochondrial respiratory chain is involved in triptolide-induced liver injury. Fitoterapia. 2011; 82: 1241-1248.

[6] Hasnat M, Yuan Z, Naveed M, Khan A, Raza F, Xu D, et al. Drp1-associatedmitochondrial dysfunction and mitochondrial autophagy: a novel mechanism in triptolide-induced hepatotoxicity. Cell Biol Toxicol. 2019; 35: 267-280.

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