1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1-blocker, inhibits both growth and metastasis of human pancreatic cancer orthotopic xenografts in mice
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- Hennig Rene
- Department of General and Visceral Surgery, Freudenstadt University Hospital, Freudenstadt, Germany.
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- Albawardi Alia
- Department of Pathology, United Arab Emirates University, Al Ain, UAE.
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- Almarzooqi Saeeda
- Department of Pathology, United Arab Emirates University, Al Ain, UAE.
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- Haneefa Shoja
- Department of Physiology, United Arab Emirates University, Al Ain, UAE.
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- Imbaraj Edward
- Department of Physiology, United Arab Emirates University, Al Ain, UAE.
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- Zaaba Nur Elena
- Department of Physiology, United Arab Emirates University, Al Ain, UAE.
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- Nemmar Abderrahim
- Department of Physiology, United Arab Emirates University, Al Ain, UAE.
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- Subramanya Sandeep
- Department of Physiology, United Arab Emirates University, Al Ain, UAE.
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- Maruta Hiroshi
- PAK Research Center, Melbourne, Australia.
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- Adrian Thomas E.
- Department of Physiology, United Arab Emirates University, Al Ain, UAE. Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE.
書誌事項
- タイトル別名
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- 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
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説明
<p>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 IC50 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.</p>
収録刊行物
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- Drug Discoveries & Therapeutics
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Drug Discoveries & Therapeutics 13 (5), 248-255, 2019-10-31
特定非営利活動法人 バイオ＆ソーシャル・サイエンス推進国際研究交流会