MyeloRx LLC
The Triptolide Company ™
Your Subtitle text

Mechanism of Action

Until recently a well-defined target had not been identified for triptolide even though a number of studies have implicated RNA polymerase ll as one likely possibility. In early January 2011, a paper was published by investigators at Johns Hopkins in Nature Chemical Biology entitled “XPB, a subunit of TFllH, is a target of the natural product triptolide.” 

XPB is one of a group of enzymes termed helicases, which are able to affect the function of DNA and RNA. They play a major role in DNA repair via a cellular mechanism termed “nuclear excision repair” or “NER” as well as modulating transcription. Mutations of XPB lead to genetic disorders such as xeroderma pigmentosum (XP), which are characterized by sensitivity to sunlight due to an inability to repair UV-induced DNA damage.

Implications of XPB blockade for cancer therapy

Two major cellular processes are affected by inhibition of XPB, DNA repair and cell signaling pathways. Both are critical for controlling tumor cell growth. 

1. DNA repair- By blocking nuclear excision repair any anti-cancer strategy targeting DNA should be enhanced when used in combination with a triptolide-based drug. As mentioned above patients with XP are especially prone to the DNA damaging effects of UV-radiation. A series of papers were published over the past few years demonstrating that triptolide enhanced the effects of radiation treatment in murine models of pancreatic cancer. Similarly triptolide-based agents have been shown to enhance the effects of drugs targeting DNA such as topoisomerase 1 inhibitors and those containing platinum.  One could envision using a triptolide-based compound as a radiation sensitizer as well as in combination with many cytotoxic agents currently available.

2. Cell signaling pathways- Proliferation of leukemic and other cancer cells is due to an overabundance of growth signals and a loss of growth inhibitors. Nuclear factor-kappa B (NF-kB) is an example of a growth promoter and is overexpressed in AML, CML, and other leukemias as well as in many solid tumors. In addition to growth stimulatory factors, inhibitors of cell proliferation have received increasing attention over the last decade. These prevent the normal apoptotic pathways from removing over-proliferating cells. Key among them are Bcl-2 (B-cell lymphoma-2), XIAP (X-linked inhibitor of apoptosis protein) and Mcl-1 (myeloid cell leukemia sequence 1). Triptolide appears unique among anti-cancer agents in that it reduces the signals stimulating cell proliferation (e.g., NF-kB) and reduces key anti-apoptotic proteins (XIAP and Mcl-1). By blocking XPB as demonstrated in the paper the resultant inhibition of RNA polymerase ll leads to these multiple effects on the signaling pathways driving cancer cell proliferation. It is therefore more efficacious than an agent targeting a single receptor or a single downstream target. The activity appears quite broad in that triptolide is capable of blocking proliferation of all of the cells in the NCI 60 cell panel with activity in the low nanomolar range. 

Back to Development Portfolio