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Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer

Key Points

  • Synthetic oleanane triterpenoids are a new class of non-cytotoxic and highly multifunctional drugs that have applications for the prevention and treatment of not only cancer, but also of many other diseases with an inflammatory component.

  • Synthetic oleanane triterpenoids are anti-inflammatory and cytoprotective, induce the differentiation of tumour cells, suppress the growth of tumour cells and are effective agents for the induction of apoptosis in cancer cells that are resistant to conventional chemotherapeutic agents.

  • Synthetic oleanane triterpenoids have been shown to be highly effective in many in vivo models for the prevention and treatment of cancer. These studies include the suppression of tumour growth in immunocompromised mice, as well as the prevention of primary lung cancer induced by a chemical carcinogen.

  • Molecular targets of synthetic oleanane triterpenoids include KEAP1 (the inhibitor of the transcription factor, NRF2), IκB kinase, transforming growth factor-β signalling and signal transducer and activator of transcription (STAT) signalling.

  • The molecular mechanism of action of the triterpenoids is believed to be mediated by Michael addition with active nucleophilic groups on proteins, such as the -SH groups on cysteine residues.

  • Rexinoids are molecules that selectively bind to the nuclear receptors known as retinoid X receptors. These receptors interact heterodimerically with many other members of the nuclear steroid receptor superfamily, and therefore have the ability to modulate the action of many steroid-like hormonal agents.

  • Great advances have been made in the synthesis of new rexinoids. These agents are highly potent, non-cytotoxic and do not have many of the toxic effects associated with classical retinoids, making them safer agents to use in the clinic.

  • Both synthetic oleanane triterpenoids and rexinoids exert their effects through multiple signalling pathways and have the potential to be used synergistically to control the inflammatory process, as well as deregulated growth associated with cancer.

Abstract

Synthetic oleanane triterpenoids and rexinoids are two new classes of multifunctional drugs. They are neither conventional cytotoxic agents, nor are they monofunctional drugs that uniquely target single steps in signal transduction pathways. Synthetic oleanane triterpenoids have profound effects on inflammation and the redox state of cells and tissues, as well as being potent anti-proliferative and pro-apoptotic agents. Rexinoids are ligands for the nuclear receptor transcription factors known as retinoid X receptors. Both classes of agents can prevent and treat cancer in experimental animals. These drugs have unique molecular and cellular mechanisms of action and might prove to be synergistic with standard anti-cancer treatments.

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Figure 1: Structures of triterpenoids.
Figure 2: Triterpenoids can protect cells and tissues from stress (inflammatory, metabolic, oxidative and nitrosative) by increasing the transcriptional activity of NRF2.
Figure 3: SO can prevent lung cancer in mice exposed to a potent carcinogen.
Figure 4: The interaction between thiol groups and SO.
Figure 5: Biological responses to SO are strongly dependent on dose.
Figure 6: Structures of rexinoids.

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Acknowledgements

We acknowledge the special contributions of our collaborators, T. Honda and G. Gribble, in the synthesis of new triterpenoids; chemical synthesis will be the subject of another review. We are indebted to W. Lamph for his pioneering contributions in the area of rexinoid research, and for his continuing encouragement of research in this area. We thank L. Wakefield for helpful suggestions and comments, M. Padgett for expert editorial and stylistic assistance in the preparation of this manuscript, and Darlene Royce for the photographs in figure 3. The spectral shift shown in figure 4 was first observed by Y. Wang (unpublished Ph.D. thesis, Dartmouth, 2001). Fiscal support for our research has been provided by the US National Cancer Institute, National Foundation for Cancer Research, Reata Pharmaceuticals and members of the Dartmouth College Class of 1934.

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Liby, K., Yore, M. & Sporn, M. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7, 357–369 (2007). https://doi.org/10.1038/nrc2129

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