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Howard D. Beall
Professor

Phone: (406) 243-5112

Email: howard.beall@umontana.edu

Howard Beall arrived at The University of Montana in July 1997 as an Assistant Professor. He earned a Ph.D. in Medicinal Chemistry at the University of Florida in 1991 under the supervision of Professor Kenneth Sloan. He completed postdoctoral training in biochemical and molecular toxicology under the guidance of Professor David Ross at the University of Colorado Health Sciences Center and served there as an Assistant Research Professor and Assistant Professor before coming to UM. He was promoted to Associate Professor in September 2000.

RESEARCH STATEMENT

Our research program bridges the general areas of toxicology and medicinal chemistry. Our interests are in (1) environmental agents and cardiovascular disease, (2) anticancer drug discovery, and (3) cancer prevention.

  1. Cardiovascular toxicity of arsenic and arsenic-metal mixtures - Arsenic exposure has been linked to cardiovascular diseases, but few studies have examined the mechanisms involved. Our interests are in reactive oxygen and nitrogen species generated by cells in response to arsenic exposure, the regulatory molecules and pathways involved in atherosclerosis, and the effect of mixtures on toxicity.

  2. NQO1-directed anticancer drug discovery - NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase) is an enzyme that is highly overexpressed in many tumors and preneoplastic tissues. We are studying the role of NQO1 in the bioreductive activation of a range of novel antitumor quinones that are structurally similar to naturally occurring anticancer compounds. Activation by NQO1 produces toxic metabolites that can selectively inhibit growth of tumor cells that have elevated NQO1 activity.

  3. Diet and cancer prevention - The principal function of phase II enzymes such as glutathione-S-transferase is to metabolically deactivate toxic substances including cancer-causing chemicals. A number of cancer preventive (chemopreventive) compounds are known to induce expression of phase II enzymes and provide protection from the initiation step of carcinogenesis. Our goal is to identify potential chemopreventive agents from dietary sources that elevate phase II gene expression and enzymatic activity. We are also interested in the role of cyclooxygenase-2 in tumor promotion, tumor progression and tumor angiogenesis.
KEY PUBLICATIONS

Newsome, J.J., Colucci, M.A., Hassani, M., Beall, H.D. and Moody, C.J. Benzimidazole- and benzothiazole-quinones: excellent substrates for NAD(P)H:quinone oxidoreductase 1. Org. Biomol. Chem., in press (2007).

Beall, H.D. and Coffin, J.D. Toxicology and the Endothelium. In: Endothelial Biomedicine (Ed. Aird WC), Cambridge University Press, New York, pp. 527-535 (2007).

He, W., Greenwell, R.J., Brooks, D.M., Calderon-Garciduenas, L., Beall, H.D. and Coffin, J.D. Arsenic exposure in pregnant mice disrupts placental vasculogenesis and causes spontaneous abortion. Toxicol. Sci. 99:244-253 (2007).

Newsome J.J., Swann, E., Hassani, M., Bray, K.C., Slawin, A.M.Z., Beall, H.D. and Moody, C.J. Indolequinone antitumor agents: correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase. Org. Biomol. Chem. 5:1629-1640 (2007).

Pereira, F.E., Coffin, J.D. and Beall, H.D. Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite – potential mechanism in the development of atherosclerosis. Toxicol. Appl. Pharmacol. 220:164-177 (2007).

Bunderson, M., Pereira, F., Schneider, M.C., Shaw, P.K., Coffin, J.D. and Beall, H.D. Manganese enhances peroxynitrite and leukotriene E4 formation in bovine aortic endothelial cells exposed to arsenic. Cardiovasc. Toxicol. 6:15-23 (2006).

Hassani, M., Cai, W., Holley, D.C., Lineswala, J.P., Maharjan, B.R., Ebrahimian, G.R., Seradj, H., Stocksdale, M.G., Mohammadi, F., Marvin, C.C., Gerdes, J.M., Beall, H.D. and Behforouz, M. Novel lavendamycin analogues as antitumor agents: synthesis, in vitro cytotoxicity, structure-metabolism and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1 (NQO1). J. Med. Chem. 48:7733-7749 (2005).

Bunderson, M., Brooks, D.M., Walker, D.L., Rosenfeld, M.E., Coffin, J.D. and Beall, H.D. Arsenic exposure exacerbates atherosclerotic plaque formation and increases nitrotyrosine and leukotriene biosynthesis. Toxicol. Appl. Pharmacol. 201:32-39 (2004).

Fryatt, T., Pettersson, H.I., Gardipee, W.T., Bray, K.C., Green, S.J., Slawin, A.M.Z., Beall, H.D. and Moody, C.J. Novel quinolinequinone antitumor agents: structure-metabolism studies with NAD(P)H:quinone oxidoreductase (NQO1). Bioorg. Med. Chem. 12:1667-1687 (2004).

Bunderson, M., Coffin, J.D. and Beall, H.D. Arsenic induces peroxynitrite generation and cyclooxygenase-2 (COX-2) protein expression in aortic endothelial cells: possible role in atherosclerosis. Toxicol. Appl. Pharmacol. 184:11-18 (2002).

Beall, H.D. and Sloan, K.B. Topical delivery of 5-fluorouracil (5-FU) by 1,3-bisalkylcarbonyl-5-FU prodrugs. Int. J. Pharm. 231:43-49 (2002).

Whatmore, J.L., Swann, E., Barraja, P., Newsome, J.J., Bunderson, M., Beall, H.D., Tooke, J.E. and Moody, C.J. Comparative study of isoflavone, quinoxaline and oxindole families of anti-angiogenic agents. Angiogenesis 5:45-51 (2002).

Swann, E., Barraja, P., Oberlander, A.M., Gardipee, W.T., Hudnott, A.R., Beall, H.D. and Moody, C.J. Indolequinone antitumor agents: correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase. Part 2. J. Med. Chem. 44:3311-3319 (2001).

Beall, H.D. and Sloan, K.B. Topical delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyl-5-FU prodrugs. Int. J. Pharm. 217:127-137 (2001).

Beall, H.D. and Winski, S.L. Mechanisms of action of quinone-containing alkylating agents: NQO1-directed drug development. Front. Biosci. 5:d639-648 (2000).

Fryatt, T., Goroski, D.T., Nilson, Z.D., Moody, C.J. and Beall, H.D. Novel quinolinequinone antitumor agents: structure-metabolism studies with NAD(P)H:quinone oxidoreductase (NQO1). Bioorg. Med. Chem. Lett. 9:2195-2198 (1999).

Beall, H.D., Winski, S., Swann, E., Hudnott, A.R., Cotterill, A.S., O’Sullivan, N., Green, S.J., Bien, R., Siegel, D., Ross, D. and Moody, C.J. Indolequinone antitumor agents: correlation between quinone structure, rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase, and in vitro cytotoxicity. J. Med. Chem. 41:4755-4766 (1998).

Beall, H.D., Hudnott, A.R., Winski, S., Siegel, D., Swann, E., Ross, D. and Moody, C.J. Indolequinone antitumor agents: relationship between quinone structure and rate of metabolism by recombinant human NQO1. Bioorg. Med. Chem. Lett. 8:545-548 (1998).

Traver, R.D., Siegel, D., Beall, H.D., Phillips, R.M., Gibson, N.W., Franklin, W.A. and Ross, D. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br. J. Cancer 75:69-75 (1997).

Beall, H.D., Liu, Y. Siegel, D., Bolton, E.M., Gibson, N.W. and Ross, D. Role of NAD(P)H:quinone oxidoreductase (DT-diaphorase) in cytotoxicity and induction of DNA damage by streptonigrin. Biochem. Pharmacol. 51:645-652 (1996).