1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of C. elegans by down-regulating PAK1 at nM levels

Drug Discoveries & Therapeutics
Binh Cao Quan NguyenH Maruta

Abstract

PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic/ageing kinase, and its dysfunction extends the healthy lifespan of C. elegans by activating HSP16 gene. 15K is a highly cell-permeable 1,2,3-triazolyl ester of ketorolac that down-regulates both PAK1 and its down-stream COX-2 in R- and S-forms, respectively. 15K is 500-5,000 times more potent than ketorolac, an old pain-killer, inhibiting the growth of cancer cell lines with IC50 ranging 5-24 nM. Scores of natural and synthetic PAK1-blockers have been shown to extend the lifespan of small animals such as C. elegans, but none of them has been effective at nM levels. Thus, we examined in vivo effect of 15K at nM levels on the survival rate of C. elegans with or without heat-shock. Like the PAK1-deficient mutant, 15K (at 50 nM)-treated worm significantly lives longer, is far more heat-resistant and less productive (fertile) than the non-treated counterpart, with an increased expression of HSP16 gene. 15K has been proven to be among the most potent anti-cancerous and longevity-promoting PAK1-blockers, and therefore has a potential to treat a variety of solid tumours without severe side effect.

References

Nov 18, 1971·The New England Journal of Medicine·J Folkman
Jul 1, 1994·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·H Maruta, A W Burgess
Feb 8, 2006·Current Biology : CB·Dario R ValenzanoAlessandro Cellerino
Jun 4, 2014·Proceedings of the National Academy of Sciences of the United States of America·Wouter De HaesLiesbet Temmerman
May 26, 2016·Aging Cell·Mark LucanicGordon J Lithgow
Jun 24, 2016·Journal of Agricultural and Food Chemistry·Nozomi TairaShinkichi Tawata
Nov 28, 2016·European Journal of Medicinal Chemistry·Binh Cao Quan NguyenHiroshi Maruta

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Aging (Keystone)

This feed focuses on cellular aging with emphasis on the mitochondria, autophagy, and metabolic processes associated with aging and longevity. Here is the latest research on cell aging.