Dr. April Risinger's lab is focused on the discovery and preclinical development of novel natural products that have anticancer potential.
We identify new agents from natural products, including marine organisms and plants, to identify new drug leads. After discovering new agents we identify their molecular mechanisms of action. This includes identifying the cellular binding site of these compounds and how they affect the proliferation, viability and cell biology of cancer cells. We also evaluate the antitumor efficacy of these agents in animal models of cancer.
One of the most exciting classes of compounds they have isolated are the taccalonolides, which are microtubule stabilizing agents isolated from plants of the genus Tacca. Microtubule stabilizers, including the taxanes, are some of the most widely used and effective drugs employed in the treatment of human cancer, however drug resistance and toxic side effects limit their use. Similar to the effects of the taxanes, the taccalonolides cause microtubule stabilization, leading to the mitotic arrest and death of cancer cells and antitumor activity in mouse models. However, the taccalonolides have efficacy in clinically relevant drug resistant models both in vitro and in vivo, suggesting they may be useful in the treatment of drug resistant human cancers.
Although the taccalonolides possess several properties of classical microtubule stabilizers, we have discovered that they work through a distinct mechanism of action compared to all other classes of microtubule stabilizing drugs. These findings include the ability of the taccalonolides to form distinct mitotic spindle structures and their propensity to affect interphase microtubules at much lower relative concentrations than the taxanes. The latter finding is of great interest given recent studies suggesting that the anticancer effects of microtubule targeting agents may be due in large part to their interphase effects.
The recent isolation of taccalonolides with potency in the low nanomolar range provided the first indication that this class of drugs interacts directly with tubulin. Intriguingly, the kinetic profile of tubulin polymerization observed in the presence of these potent taccalonolides is unlike that observed with other stabilizers, further suggesting that the taccalonolides interact with tubulin in a manner that is markedly distinct from other classes of microtubule targeting agents. The unique biochemical and cell biological properties of these potent taccalonolides, together with the excellent in vivo antitumor activity observed for this class of agents in drug resistant tumor models, reveal the potential of the taccalonolides as a new class of anticancer drugs. Our current research is focused on identifying the taccalonolide(s) that have the greatest potential for clinical development and fully characterizing their cell biological and antitumor activities.
Lee B, Bohmann J, Reeves T, Levenson C, Risinger AL. α- and β-Santalols Directly Interact
with Tubulin and Cause Mitotic Arrest and Cytotoxicity in Oral Cancer Cells.
J Nat Prod. 2015 Jun 26;78(6):1357-62.
Du, L., Risinger, AL., King, JB., Powell, DR. and Cichewicz, RH. (2014)A Potent HDAC Inhibitor, 1-Alaninechlamydocin, from a Tolypocladium sp. Induces G2/M Cell Cycle Arrest and Apoptosis in MIA PaCa-2 Cells.Journal of Natural Products77(7):1753-7
Peng, J., Risinger, AL., Li, J. and Mooberry, SL. (2014)Synthetic reactions with rare taccalonolides reveal the value of C-22,23 epoxidation for microtubule stabilizing potency.Journal of Medicinal Chemistry57(14):6141-9
Risinger, AL., Riffle, SM., Lopus, M., Jordan, MA., Wilson, L. and Mooberry, SL. (2014)The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation.Molecular Cancer 13(1):41
Risinger, AL., Peng, J., Rohena, CC., Aguilar, HR., Frantz, DE. and Mooberry, SL. (2013)The Bat Flower: A Source of Microtubule-Destabilizing and -Stabilizing Compounds with Synergistic Antiproliferative Actions.Journal of Natural ProductsEpub Oct 2, 2013
Risinger, AL., Li, J., Bennett, MJ., Rohena, CC., Peng, J., Schriemer, DC. and Mooberry, SL. (2013)Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity.Cancer Research Epub Sep 18, 2013.