Our research interests focus on the development and application of instrumental techniques to investigate mechanistic pathways in pharmacology and pathophysiology.
Metabolisms and functions of lipids
We are interested in arachidonic acid (AA)-derived lipids and their functions in cancer and heart. Arachidonic acid can be metabolized by three groups of oxygenases, namely cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) to many biologically active eicosanoids. These enzymes and their AA metabolites have important physiological, pharmacological, and pathological roles. Another group of lipids are compounds containing an AA moiety named "endocannabinoids". Endocannabinoids are endogenously produced in many cell types and they bind to the cannabinoid receptors to initiate the cellular signaling cascade that regulate cellular functions. Two well-characterized endocannabinoids are arachidonylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG). Both AEA and 2-AG have been extensively investigated in nervous systems, however their functions in cancer are not well-understood.
(1) Regulation of prostate cancer by eicosanoids and endocannabinoids: There are strong evidence that COX-2, LOX, and their AA metabolites play important roles in the development, growth, and metastasis of many types of cancer including prostate cancer. The roles of these enzymes and their AA metabolites and the mechanisms involved in prostate cancer are still unclear. Recently, we found that 2-arachidonoylglycerol (2-AG) is produced and acts as an endogenous suppressor of proliferation and invasion in prostate carcinoma cells, through the activation of the cannabinoid receptor type-1 (CB1) signaling pathway. Our results also indicate that the enzymes synthesizing and degrading 2-AG have important roles in the regulation of the growth and invasiveness of prostate carcinoma cells. An understanding of the mechanisms of these enzymes and the CB1 receptor-mediated signaling potentially leads to new therapeutic targets to treat prostate cancer.
(2) Eicosanoids and myocardial injury: In the heart, CYP can metabolize AA to several regioisomeric epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE). EETs are then further hydrolyzed to dihydroxyeicosatrienoic acids (DHETs). EETs and DHETs are potent vasodilators and they inhibit platelet and neutrophil adhesion/aggregation. However, 20-HETE exhibits vasoconstriction effects. Very little is known about the roles of CYP and these AA metabolites in myocardial injury during ischemia-reperfusion. The concentrations of these metabolites in plasma increase during the occlusion and reperfusion of the heart. The plasma concentration of 20-HETE is significantly higher than other CYP eicosanoids. Several CYPw-hydroxylases known to produce 20-HETE are present in the heart tissue. Inhibiting the activity of these CYPw-hydroxylases and the 20-HETE production decreases myocardial infarct size. Studies using specific enzyme inhibitors will provide insights into their mechanisms and role(s) in myocardial injury and the results may lead to the development of a new class of therapeutic agents.
Selected recent publications
Nithipatikom K, Endsley MP, Moore JM, Isbell MA, Falck JR, Campbell WB, Gross GJ. Effects of Selective Inhibition of Cytochrome P450{omega}-hydroxylases and Ischemic Preconditioning in Myocardial Protection. Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H500-5. Epub 2005 Oct 7.
Gross GJ, Falck JR, Gross ER, Isbell M, Moore J, Nithipatikom K. Cytochrome P450 and arachidonic acid metabolites: Role in myocardial ischemia/reperfusion injury revisited. Cardiovasc Res. 2005 Oct 1;68(1):18-25.
Nithipatikom K, Endsley MP, Isbell MA, Wheelock CE, Hammock BD, Campbell WB. A new class of inhibitors of 2-arachidonoylglycerol hydrolysis and invasion of prostate cancer cells. Biochem Biophys Res Commun. 2005 Jul 15;332(4):1028-33.
Nithipatikom K, Endsley MP, Isbell MA, Falck JR, Iwamoto Y, Hillard CJ, Campbell WB. 2-Arachidonoylglycerol: a novel inhibitor of androgen-independent prostate cancer cell invasion. Cancer Res. 2004 Dec 15;64(24):8826-30.
Gross ER, Nithipatikom K, Hsu AK, Peart JN, Falck JR, Campbell WB, Gross GJ. Cytochrome P450 omega-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal K(ATP) channel. J Mol Cell Cardiol. 2004 Dec;37(6):1245-9.
Nithipatikom K, Gross ER, Endsley MP, Moore JM, Isbell MA, Falck JR, Campbell WB, Gross GJ. Inhibition of cytochrome P450 omega-hydroxylase: a novel endogenous cardioprotective pathway. Circ Res. 2004 Oct 15;95(8):e65-71.
Nithipatikom K, Holmes BB, McCoy MJ, Hillard CJ, Campbell WB. Chronic administration of nitric oxide reduces angiotensin II receptor type 1 expression and aldosterone synthesis in zona glomerulosa cells. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E820-7.