CURRENT RESEARCH



FIGURE 1.  Inhibitors of various transformations leading to protein prenylation. Three enzymes prenylate proteins in humans: farnesyl transferase and geranylgeranyl transferases I and II. The prenylation enzymes can be directly inhibited by farnesyl transferase inhibitors, inhibitors of geranylgeranyl transferase I or II, or dual prenyl transferase inhibitors. Alternatively, protein prenylation can be indirectly inhibited following isoprenoid diphosphate depletion with agents including statins, nitrogenous bisphosphonates, and GGDPS inhibitors. GGDPS, geranylgeranyl diphosphate synthase.
From: Wiemer AJ, Wiemer DF, Hohl RJ.  Geranylgeranyl diphosphate synthase: an emerging therapeutic target.  Clin Pharmacol Ther (Review), 90(6):804-812, 2011.  PMID: 22048229.

Dr. Hohl’s research program is focused on understanding the role of the isoprenoids, the metabolic precursors for cholesterol and other important molecular products, to not only alter cancer cell growth but to modify fundamental properties such as cancer cell migration.  His group is also assessing for the impact of manipulation of the isoprenoid biosynthetic pathway on health and disease.  A consequence of his collaboration with Professor David Wiemer in the University of Iowa’s Department of Chemistry (a link to Professor Wiemer’s website is listed in the “Collaborators” section of this site) is that his science spans from very basic organic chemistry to biochemical, cell biology, pharmacology, preclinical animal, and clinical human research.

There are two main foci for his group.  The first is evaluation the isoprenoid pathway itself.  Shown in Figure 1 is this pathway.
His group has developed analytical methods for measuring the levels of the many intermediates for this pathway in cell culture and mammalian tissues.  Small molecule inhibitors that target individual steps in this pathway have been discovered.  Some of these are being developed for pharmaceutical uses through his biotechnology University of Iowa spin-out company, Terpenoid Therapeutics Incorporated.

The second focus is on elucidating the mechanisms of action and potential therapeutic application of the isoprenoid-derived schweinfurthins.  These compounds were originally isolated from a tree indigenous to Cameroon, Africa and have activity against human brain cancer cells.  He has collaborated with investigators at the National Cancer Institute who first described the anti-cancer activity of these compounds.  The Hohl laboratory, in collaboration with Professor Wiemer’s group in Chemistry, have discovered increasingly active synthetic schweinfurthins.  Furthermore, they have developed fluorescent schweinfurthins to demonstrate where in human brain cancer cells these agents have the highest concentrations.  Shown below is a key figure demonstrating how these agents also distort the very shape of the brain cancer cells.

A, effects of schweinfurthin treatment on phalloidin staining in SF-295 cells. In this experiment, cells were left untreated (Control) or were treated with 3dSB (500 nM), 3dSB-PNBS (500 nM), DMP-PNBS (1 μM), or Y-27632 (10 μM) for 48 h. Cells were stained with 4′,6-diamidino-2-phenylindole (blue) and phalloidin (green).  B, effects of schweinfurthin treatment on phalloidin staining in A549 cells. A549 cells were left untreated (Control) or were treated with 3dSB (500 nM), 3dSB-PNBS (500 nM), DMP-PNBS (1 μM), or Y-27632 (10 μM) for 48 h. Staining conditions were as described for A.
From:  Kuder CH, Sheehy RM, Neighbors JD, Wiemer DF, Hohl RJ.  Functional evaluation of a fluorescent schweinfurthin: mechanism of cytotoxicity and intracellular quantification.  Mol Pharmacol 82(1):9-16, 2012.  PMID: 22461663

Shown above in panel A the control cells display normal architecture whereas the cells with treated with 3 deoxyschweinfurthin B (3dSB) are spindle shaped. Panel B shows a human lung cancer line that is resistant to 3dSB and it is evident that there is not the shape change. Ongoing evidence suggests that this shape change is a direct consequence of one mechanism of schweinfurthin anticancer activity. Finally, the Hohl group has been active in early phase human clinical trials of novel anticancer agents. For example, Dr. Hohl is principle investigator for a single site first time in human clinical trial of a novel anthracycline (GPX-150). This agent retains anthracycline anticancer properties without inducing cardiac toxicity.