RT Journal Article
SR Electronic
T1 Combined antiproliferative effects of the aminoalkylindole WIN55,212-2 and radiation in breast cancer cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.113.205120
DO 10.1124/jpet.113.205120
A1 Sean M Emery
A1 Moureq R Alotaibi
A1 Qing Tao
A1 Dana E. Selley
A1 Aron H. Lichtman
A1 David A. Gewirtz
YR 2013
UL http://jpet.aspetjournals.org/content/early/2013/11/20/jpet.113.205120.abstract
AB The potential antitumor activity of cannabinoid receptor agonists, such as the aminoalklylindole WIN55,212-2 (WIN2), has been studied extensively, but their potential interaction with conventional cancer therapies, such as radiation, remains unknown. In the present work, the influence of WIN2 on the antiproliferative activity of radiation in human (MCF-7 and MDA-MB231) and murine (4T1) breast cancer cells was investigated. The antiproliferative effects produced by combination of WIN2 and radiation were more effective than either agent alone. The stereoisomer of WIN2, WIN55,212-3 (WIN3), failed to inhibit growth or potentiate the growth-inhibitory effects of radiation, indicative of stereospecificity. Two other aminoalkylindoles, pravadoline and JWH-015, also enhanced the antiproliferative effects of radiation, but other synthetic cannabinoids (i.e., nabilone, CP55,940 and methanandamide) or phytocannabinoids (i.e., Δ9-tetrahydrocannabinol (THC) and cannabidiol) did not. The combination treatment of WIN2 + radiation promoted both autophagy and senescence, but not apoptosis or necrosis. WIN2 also failed to alter radiationinduced DNA damage or the apparent rate of DNA repair. While the antiproliferative actions of WIN2 were mediated through non-cannabinoid receptor mediated pathways, the observation that WIN2 interfered with growth stimulation by sphingosine-1-phosphate (S1P) implicates the potential involvement of S1P/ceramide signaling pathways. In addition to demonstrating that aminoalkylindole compounds could potentially augment the effectiveness of radiation treatment in breast cancer, the present study suggests that THC and nabilone are unlikely to interfere with the effectiveness of radiation therapy, which is of particular relevance to patients using cannabinoid-based drugs to ameliorate the toxicity of cancer therapies.