title: EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade.
abstract: To determine whether the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation, and cardiac stress, erlotinib was administered to rats (10 mg · kg(-1)· d(-1)) for 9 weeks. Plasma magnesium decreased progressively between 3 and 9 weeks (-9% to -26%). Modest increases in plasma substance P (SP) occurred at 3 (27%) and 9 (25%) weeks. Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac perivascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg · kg(-1) · d(-1)), attenuated erlotinib-induced hypomagnesemia up to 42%, reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished. Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (-11%) and % fractional shortening (-17%) by 7 weeks of erlotinib treatment and significant reduction (-17.5%) in mitral valve E/A ratio at week 9 indicative of systolic and early diastolic dysfunction. Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy. Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction and partially attenuated the anatomical changes. Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress and mild-to-moderate cardiac dysfunction, which can largely be corrected by the administration of the SP receptor blocker.
authors.affiliation: *Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC; †Division of Cardiology, Children's National Medical Center, Washington, DC; and ‡Department of Medicine, The George Washington University, Washington, DC.
authors.forename: I Tong
authors.initials: IT
authors.lastname: Mak
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kramer
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Chmielinska
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: William B
authors.initials: WB
authors.lastname: Weglicki
mesh_terms: D000818:Animals; D000077608:Aprepitant; D004452:Echocardiography; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D008274:Magnesium / Q000097:blood; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D013373:Substance P; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D008274:Magnesium