Triptolide is a

diterpenoid Diterpenes are a class of chemical compounds composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being ...

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

which is produced by the thunder god vine, ''

Tripterygium wilfordii ''Tripterygium wilfordii'', or ''léi gōng téng'' (Mandarin) (, Japanese: ''raikōtō''), sometimes called thunder god vine but more properly translated thunder duke vine, is a vine used in traditional Chinese medicine. ''Tripterygium wilfordi ...

''. It has ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...

'' activities against

mouse model A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...

s of

polycystic kidney disease Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These c ...

and

pancreatic cancer Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancr ...

, but its

physical properties A physical property is any property that is measurable, whose value describes a state of a physical system. The changes in the physical properties of a system can be used to describe its changes between momentary states. Physical properties are ...

and severe toxicity limit its therapeutic potential. Consequently, a synthetic water-soluble

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

, minnelide, is being studied clinically instead. Triptolide is a component of

ContraPest ContraPest is the first U.S. EPA registered contraceptive pest control tool designed to reduce fertility in brown and black rats, developed by the U.S. biotechnology company SenesTech. It is a flavored liquid, designed to be attractive to, and ...

, a

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

pest control Pest control is the regulation or management of a species defined as a pest; any animal, plant or fungus that impacts adversely on human activities or environment. The human response depends on the importance of the damage done and will range ...

liquid used to reduce rat populations in the United States.

Mechanism of action

Several putative target proteins of triptolide have been reported, including

polycystin-2 Polycystin-2 is a protein that in humans is encoded by the ''PKD2'' gene. This gene encodes a member of the polycystin protein family, called TRPP2, previously known as polycystin-2, PC2 or APKD2. TRPP2 contains multiple transmembrane domains, ...

ADAM10 A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ''ADAM10'' gene. Function Members of the ADAM family are cell surface proteins with a un ...

, DCTPP1,

TAB1 Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the ''TAB1'' gene. Function The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinase MAP3K7 ...

, and

XPB XPB (xeroderma pigmentosum type B) is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex. Structure The 3D-structure of the archaeal homolog of XPB has been solved by X-ray crystallography by Dr. J ...

. Multiple triptolide-resistant mutations exist in XPB (ERCC3) and its partner protein

GTF2H4 General transcription factor IIH subunit 4 is a protein that in humans is encoded by the ''GTF2H4'' gene. Interactions GTF2H4 has been shown to interact with: * GTF2F1, * MED21, * POLR2A, * TATA binding protein, * Transcription Factor I ...

.Y. Smurnyy, M. Cai, H. Wu, E. McWhinnie, J. A. Tallarico, Y.Yang, Y. Feng, DNA sequencing and CRISPR-Cas9 gene editing for target validation in mammalian cells. ''Nat. Chem. Biol''. 2014, 10, 623 – 625 However, no triptolide-resistant mutations were found in polycystin-2, ADAM10, DCTPP1 and TAB1. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13-epoxide group of triptolide, and the XPB-C342T mutant rendered the T7115 cell line nearly completely resistant to triptolide.Q. L. He, D. V. Titov, J. Li, M. Tan, Z. Ye, Y. Zhao, D. Romo, and J. O. Liu. Covalent Modification of a Cysteine Residue in the XPB Subunit of the General Transcription Factor TFIIH Through Single Epoxide Cleavage of the Transcription Inhibitor Triptolide. ''Angew. Chem. Int. Ed.'' 2015, 54, 1859 –1863 The level of resistance conferred by the C342T mutation is about 100-fold higher than the most triptolide-resistant mutants previously identified. Together, these results validate XPB as a target responsible for the antiproliferative activity of triptolide. The disruption of

super-enhancer In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity. Because super-enhance ...

networks Network, networking and networked may refer to: Science and technology * Network theory, the study of graphs as a representation of relations between discrete objects * Network science, an academic field that studies complex networks Mathematics ...

has also been suggested as a mechanism of action.

Water-soluble prodrugs

Minnelide is a more water-soluble synthetic

of triptolide which is converted to triptolide ''

''.Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012
/ref> In a preclinical mouse model of pancreatic cancer, it was "even more effective than

gemcitabine Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by ...

". Its

Phase II clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

are expected to conclude in February 2019. Minnelide_structure

Glutriptolide, a glucose conjugate of triptolide with better solubility and lower toxicity, did not inhibit XPB activity ''in vitro'', but exhibited tumor control ''in vivo'', which is likely due to sustained stepwise release of active triptolide within cancer cells. A second generation glutriptolide has been recently reported for targeting hypoxic cancer cells with increased glucose transporter expression.

References

{{Expand German, Triptolid, date=October 2012 Diterpenes Epoxides Furanones Secondary alcohols Isopropyl compounds