Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid

Citation
Ld. Recht et al., Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid, BIOCH PHARM, 62(6), 2001, pp. 755-763
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
6
Year of publication
2001
Pages
755 - 763
Database
ISI
SICI code
0006-2952(20010915)62:6<755:AEOAA(>2.0.ZU;2-N
Abstract
One of the endogenous transformation products of tetrahydrocannabinol (THC) is THC-11-oic acid, and ajulemic acid (AJA; dimethylheptyl-THC- 11-oic aci d) is a side-chain synthetic analog of THC-11-oic acid. In preclinical stud ies, AJA has been found to be a potent anti-inflammatory agent without psyc hoactive properties. Based on recent reports suggesting antitumor effects o f cannabinoids (CBs), we assessed the potential of AJA as an antitumor agen t. AJA proved to be approximately one-half as potent as THC in inhibiting t umor growth in vitro against a variety of neoplastic cell lines. However, i ts in vitro effects lasted longer. The antitumor effect was stereospecific, suggesting receptor mediation. Unlike THC, however, whose effect was block ed by both CB1 and CB2 receptor antagonists, the effect of AJA was inhibite d by only the CB2 antagonist. Additionally, incubation of C6 glioma cells w ith AJA resulted in the formation of lipid droplets, the number of which in creased over time; this effect was noted to a much greater extent after AJA than after THC and was not seen in WI-38 cells, a human normal fibroblast cell line. Analysis of incorporation of radiolabeled fatty acids revealed a marked accumulation of triglycerides in AJA-treated cells at concentration s that produced tumor growth inhibition. Finally, AJA, administered p.o. to nude mice at a dosage several orders of magnitude below that which produce s toxicity, inhibited the growth of subcutaneously implanted U87 human glio ma cells modestly but significantly. We conclude that AJA acts to produce s ignificant antitumor activity and effects its actions primarily via CB2 rec eptors. Its very favorable toxicity profile, including lack of psychoactivi ty, makes it suitable for chronic usage. Further studies are warranted to d etermine its optimal role as an antitumor agent. (C) 2001 Elsevier Science Inc. All rights reserved.