Down-regulation of 20-HETE synthesis and signaling inhibits renal adenocarcinoma cell proliferation and tumor growth.
BACKGROUND
We examined the ability of inhibitors of the synthesis or actions of 20-HETE, metabolite of arachidonic acid, to inhibit proliferation of human renal carcinoma cell lines.


METHODS
786-O and 769-P cells were exposed to either 10 microM HET0016 (selective inhibitor of 20-HETE synthesis), 10 microM WIT002 (20-HETE antagonist), or vehicle. Subsequently, we assessed the effect of WIT002 on tumor growth in vivo using an ectopic mouse model of clear-cell renal carcinoma.


RESULTS
Addition of HET0016 and WIT002 inhibited the proliferation of 786-O and 769-P human renal cell carcinoma lines. HET0016 and WIT002 had little effect on the proliferation of primary cultures of normal human proximal tubule epithelial cells. WIT002 (10 mg/kg, s.c.) administered daily to athymic nude mice implanted subcutaneously with 786-O cells reduced the growth of the tumors by 84 % compared to vehicle (p<0.001).


CONCLUSIONS
20-HETE is required for proliferation of human renal epithelial cancer.
Kidney Disease Center, Department of Medicine and Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Anna
A
Alexanian
Victoriya A
VA
Rufanova
Bradley
B
Miller
Averia
A
Flasch
Richard J
RJ
Roman
Andrey
A
Sorokin
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000578:Amidines; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C465349:CYP4F3 protein, human