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 other cellular systems and organs are less 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. However, the mechanisms that these eicosanoids regulate prostate cancer are still unclear. We have been investigating the roles of these compounds in prostate cancer progression. Recently, we found that the endocannabinoid, 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. Enzymes that metabolize 2-AG have critical effects on how 2-AG control growth and invasiveness of prostate carcinoma cells by reducing the actions of 2-AG and liberating free AA for synthesis of eicosanoids. An understanding of the mechanisms of these enzymes and the CB1 receptor activation signaling pathways 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. EETs reduce but 20-HETE enhances myocardial injury during ischemia-reperfusion. The concentrations of these metabolites in plasma increase during the occlusion and reperfusion of the heart. Inhibiting the activity of these CYPw-hydroxylases and the 20-HETE production decreases myocardial infarct size. Similarly, exogenously administered EETs markedly reduce 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, 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
Endsley MP, Aggarwal N, Isbell MA, Wheelock CE, Hammock BD, Falck JR, Campbell WB, Nithipatikom K. Diverse roles of 2-arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12-lipoxygenase metabolism. Int J Cancer 2007 Sep 1;121(5):984-91.
Cui L, Isbell MA, Chawengsub Y, Falck JR, Campbell WB, Nithipatikom K. Structural Characterization of Monohydroxyeicosatetraenoic Acids and Dihydroxy- and Trihydroxyeicosatrienoic Acids by ESI-FTICR. J Am Soc Mass Spec 2008 Apr;19(4):569-85.
Endsley MP, Thill R, Choudhry I, Williams CL, Kajdacsy-Balla A, Campbell WB, Nithipatikom K. Expression and Function of Fatty Acid Amide Hydrolase in Prostate Cancer. Int J Cancer 2008 Sep 15;123(6):1318-26.
Gross GJ, Gauthier KM, Moore J, Falck JR, Hammock BD, Campbell WB, Nithipatikom. Effects of the Selective EET Antagonist, 14,15-EEZE, on Cardioprotection Produced by Exogenous or Endogenous EETs in the Canine Heart. Am J Physiol Heart Circ Physiol 2008 Jun; 294(6):H2838-44.
Gross GJ, Gauthier KM, Moore J, Campbell WB, Falck JR, Nithipatikom K. Evidence for a Role of Epoxyeicosatrienoic Acids (EETs) in Mediating Ischemic Preconditioning and Postconditioning in Dog. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H47-52.
Gross GJ, Baker JE, Hsu A, Wu, Falck JR, Nithipatikom K. Evidence for a Role of Opioids in Epoxyeicosatrienoic Acid (EET)-induced Cardioprotection in Rat Hearts. Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2201-7.