%0 Journal Article
%T 1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice.
%A Adrian TE
%A Albawardi A
%A Almarzooqi S
%A Hennig R
%A Maruta H
%A Nemmar A
%A Samuel E
%A Shoja MH
%A Subramanya S
%A Zaaba NEB
%J Drug Discoveries & Therapeutics
%D -1
%R Drug Discov Ther. 2019 ;13(5):248-255. (DOI: 10.5582/ddt.2019.01068)
%X ABSTRACT: More than 90% of human pancreatic cancers carry the oncogenic mutant of Ki-RAS and their growth depends on its downstream kinase PAK1, mainly because PAK1 blocks the apoptosis of cancer cells selectively. We developed a highly cell-permeable PAK1-blocker called 15K from an old pain-killer (ketorolac), that is shown here to inhibit the growth of three pancreatic cancer cell lines with IC 50 values ranging 41-88 nM in vitro. The anti-cancer effect of 15K was further investigated in an orthotopic xenograft model with gemcitabine (GEM)-resistant human pancreatic cancer cell lines (AsPC-1 and BxPC-3) expressing luciferase in athymic mice. During 4 weeks, 15K blocks total burden (growth) of both AsPC-1 and BxPC-3 tumors (measured as radians/sec) with the IC50 below daily dose of 0.1 mg/kg, i.p. In a similar manner 15K reduced both their invasion and metastases as well, while it had no effect on either body weight or hematological parameters even at 5 mg/kg/day. To the best of our knowledge, 15K is so far the most potent among synthetic PAK1-blockers in vivo, and could be potentially useful for therapy of GEM-resistant cancers. Key Words: 1,2,3-Triazolyl ester of ketorolac (15K), PAK1, pancreatic cancer, gemcitabine resistance, xenografts Full Text: PDF(891KB
%U http://www.ddtjournal.com/getabstract.php?id=1789