Cancer chemopreventive action of α-(-)-bisabolol, a sesquiterpene alcohol involves inhibition of cathepsin D and ornithine decarboxylase via tramping nitric oxide

Abstract

AbstractTerpenoids, traditionally used for cosmetic and medicinal purposes, are currently being explored as cancer chemopreventive as well as chemotherapeutic agent in clinical trials. α-(-)-bisabolol, a naturally occurring monocyclic sesquiterpene alcohol is a major component of essential oil of chamomile (Matricaria recutita L., Chamomilla recutita L., Matricaria chamomilla; Family Asteraceae). As substantiated previously, α-(-)-bisabolol is known to have antimicrobial, anti-irritant, anti-inflammatory and anti-allergic properties. It also affects cell viability and growth of various human and murine cell lines by either inducing apoptosis or suppressing Akt activation or down regulating expression of some genes implicated in carcinogenesis. To elucidate the possible mechanism for its cancer chemopreventive action, herein we are reporting dose-dependent effect of α-(-)-bisabolol on ornithine decarboxylase (ODC, a key rate limiting enzyme in mammalian polyamine biosynthesis), cathepsin D (CATD, a lysosomal aspartyl protease) and dihydrofolate reductase (DHFR, a protein of purine biosynthetic pathway) all of these proteins get over-expressed during cell transformation, proliferation and malignancy. Our results demonstrate greater activity of α-(-)-bisabolol by exhibiting potent inhibition of ODC (99% at a concentration of 100μM with an IC50 value of 0.01μM) and CATD (22% at 10μM). The molecule did not affect DHFR activity significantly. To establish the hypothesis whether inhibition of CATD and ODC involves tramping of nitric oxide (NO), we have also investigated the scavenging potential of α-(-)-bisabolol and the results were found to be promising with an IC50 of 0.1μM. Our findings suggest that α-(-)-bisabolol not only inhibits ODC and CATD activity through scavenging of NO radicals but also exerts anti-tumour promoting properties which may perhaps be due to channeling of arginine in the NO and polyamine biosynthesis pathways. These results provide a possibility of developing α-(-)-bisabolol as a viable cancer chemopreventive agent.