Fighting cancer with triptolide

“My cancer is me. The tumours are made of me. They’re made of me as surely as my brain and my heart are made of me. It is a civil war with a predetermined winner”.

― John Green, The Fault in Our Stars

Triptolide is a natural constituent derived from the root of a plant (a vine) called Tripterygium wilfordii Hook. F. or thunder god vine or more properly translated thunder duke vine used in traditional Chinese medicine, which possesses diverse effects including anti-inflammatory, anti-oxidative and anti-cancer activities. While the plant itself is poisonous, the root is a source of various biologically active compounds. But thunder god vine contains also chemicals that might decrease male fertility.

In particular for cancer therapy, triptolide has been used to treat breast, lung, bladder, liver, colorectal, pancreatic, ovarian, stomach, prostate, cervical and oral cancers, melanoma, myeloma, leukemia, neuroblastoma, osteosarcoma, lymphoma, renal (Source: "Fighting renal cell carcinoma with natural compounds backed by science"), nasopharyngeal and endometrial carcinoma; through apoptosis, cell cycle arrest, inhibition of cell proliferation, metastasis and angiogenesis (Source: "Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine").

For example, triptolide can mediate apoptosis in Burkitt’s lymphoma Raji (lymphoblast-like cells), NAMALWA (B lymphocyte) and Daudi cells (B lymphoblasts), and inhibits tumour growth in Daudi xenograft mice as well cell proliferation through microRNA-181a up-regulation (often regarded as an oncogene in tumours) in human neuroblastoma cells.

Moreover, triptolide can induce apoptosis and inhibit angiogenesis (Source: "Fighting angiogenesis with natural compounds backed by science") in human osteosarcoma cells and breast cancer cells (Source: "Fighting breast cancer with natural compounds backed by science"). In addition, triptolide is able to inhibit cell migration and invasion in human prostate cancer cells, and in tongue squamous cell carcinoma cells co-inoculated with human monocytes cells.

Triptolide exerts its anti-cancer effects through multiple targets

Triptolide can induce mitochondrial-mediated apoptosis in various cancer cells through

• decreased mitochondrial membrane potential (is a signal of bioenergetic stress and may result in the release of apoptotic factors leading to cell death),
• cytochrome c accumulation (cytochrome C is a mitochondrial protein that induces apoptosis when released into the cytosol),
• PARP (Poly ADP-ribose polymerase or PARP is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability and programmed cell death) and
• caspase-3 activation.

Moreover, ERK (the MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell) is also shown to be important in mediating triptolide-induced anti-cancer activities. In particular, triptolide induces apoptosis through ERK activation in human breast cancer cells, and ERK activation leads to caspase activation (activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues). On the other hand, it can also inhibit metastasis through ERK down-regulation in esophageal squamous cancer cells and murine melanoma cells.

Interestingly, estrogen receptor alpha is shown to be a potential binding protein of triptolide and its analogues.

Triptolide and immune system

For example, the combined use of triptolide and cisplatin (a chemotherapy medication used to treat testicular, ovarian, cervical, breast, bladder, head and neck, esophageal and lung cancer, mesothelioma, brain tumours and neuroblastoma) enhances the plasma levels of

• IL-2 (an interleukin that regulates the activities of white blood cells leukocytes and often lymphocytes, that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self") and
• TNF-α (as a cytokine, TNF is used by the immune system for cell signaling. mTNF-α is mainly found on monocytes/macrophages and is able to induce fever, apoptotic cell death, cachexia, and inflammation, inhibit tumorigenesis and viral replication)

in ovarian cancer xenograft mice, which can promote the differentiation of T cells and inhibit tumorigenesis respectively, thus resulting in an inflammatory microenvironment and leading to cancer cell death.

Triptolide derivatives and analogs in clinical studies

Different triptolide derivatives exist for example:

• MRx102, shows positive effects on anti-proliferation and anti-metastasis in human non-small-cell lung carcinoma cells, and xenograft mice.
• Minnelide, a water-soluble pro-drug of triptolide, can inhibit tumour growth in pancreatic cancer xenograft mice, while, the combination of minnelide and oxaliplatin further inhibits tumour growth.
• Triptolide loaded onto a peptide fragment (TPS-PF-A299–585) is specifically targeted to the kidney and has less toxicity. In general, triptolide is poorly soluble in water and exhibits hepatotoxicity and nephrotoxicity, therefore selective delivery is an effective strategy for further application in cancer treatment.
• Triptolide-loaded liposomes are reported also to contribute a targeted delivery with lower toxicity and better efficacy in lung cancer treatment.
• Triptolide-loaded exosomes can also enhance apoptosis in human ovarian cancer cells.

In particular, minnelide was used in a phase I clinical trial with patients with refractory gastrointestinal malignancies to study the dose escalation (0.16 to 0.8 mg/m) and pharmacokinectics of minnelide, and the doses were well tolerated except from the common hematologic toxicity. Finally, minnelide is currently under phase II clinical trial to test anti-cancer effects in patients with advanced pancreatic cancer.

Triptolide combined treatments 💊

Triptolide combined with gemcitabine (a chemotherapy medication to treat cancers including testicular, breast, ovarian, non-small cell lung, pancreatic and bladder cancer) markedly enhances pro-apoptosis in human bladder cancer cells.

Triptolide plus ionising radiation synergistically enhances apoptosis and anti-angiogenic effects in human nasopharyngeal carcinoma cells and xenograft mice, which provides a new chemotherapy to advanced nasopharyngeal malignancy. The combined therapy of triptolide and 5- fluorouracil (is a cytotoxic chemotherapy medication used by intravenous injection for treatment of colorectal, oesophageal, stomach, pancreatic, breast and cervical cancer, and as a cream it is used for actinic keratosis, basal cell carcinoma and skin warts) further promotes apoptosis and inhibits tumour growth in human pancreatic cancer cells and xenograft mice.

Finally, low concentration of triptolide potentiates cisplatin-induced apoptosis in human lung cancer cells, and triptolide with cisplatin (a chemotherapy medication used to treat testicular, ovarian, cervical, breast, bladder, head and neck, esophageal and lung cancer, mesothelioma, brain tumors and neuroblastoma) synergistically enhances apoptosis and induces cell cycle arrest in human bladder cancer cisplatin-resistant cells.

Thanks for reading 💙👓

P.S.

There are more than 300,000 plant species 🌵🌴🌳🌲🌱🌿☘🍀🍃🍂🍁🌻🌺🌾 identified to date, and the list is constantly expanding.