Background: Our previous screening efforts with
colorectal cancer cell lines suggested potential
cannabinoid therapeutic leads for other solid
cancers. Objectives: The aim of this study was to identify
cannabinoid lead compounds that have
cytostatic and cytocidal activities against prostate and
pancreatic cancer cell lines and profile cellular responses and molecular pathways of select leads. Materials and Methods: A library of 369 synthetic
cannabinoids was screened against 4 prostate and 2
pancreatic cancer cell lines with 48 h of exposure at 10 μM in medium with 10%
fetal bovine serum using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay. Concentration titration of the top 6 hits was carried out to identify their concentration-response patterns and calculate IC50 values. Three select leads were examined for cell cycle, apoptosis, and autophagy responses. The role of
cannabinoid receptors (CB1 and CB2) and noncanonical receptors in apoptosis signaling was examined with selective antagonists. Results: Two independent screening experiments in each cell line detected growth inhibitory activities against all six or a majority of
cancer cell lines for
HU-331 (a known
cannabinoid topoisomerase II inhibitor), (±)5-epi-CP55,940, and PTI-2, each previously identified in our
colorectal cancer study. 5-Fluoro NPB-22, FUB-NPB-22, and
LY2183240 were novel hits. Morphologically and biochemically, (±)5-epi-CP55,940 elicited
caspase-mediated apoptosis of PC-3-luc2 (a PC-3 subline with
luciferase)
prostate cancer and Panc-1
pancreatic cancer cell lines, each the most aggressive of the respective organ site. The apoptosis induced by (±)5-epi-CP55,940 was abolished by the CB2 antagonist,
SR144528, but not modulated by the CB1 antagonist,
rimonabant, and GPR55 antagonist, ML-193, nor TRPV1 antagonist,
SB-705498. In contrast, 5-fluoro NPB-22 and FUB-NPB-22 did not cause substantial apoptosis in either cell line, but resulted in cytosolic vacuoles and increased LC3-II formation (suggestive of autophagy) and S and G2/M cell cycle arrests. Combining each fluoro compound with an autophagy inhibitor,
hydroxychloroquine, enhanced the apoptosis. Conclusions: 5-Fluoro NPB-22, FUB-NPB-22, and
LY2183240 represent new leads against prostate and
pancreatic cancer cells in addition to the previously reported compounds,
HU-331, (±)5-epi-CP55,940, and PTI-2. Mechanistically, the two fluoro compounds and (±)5-epi-CP55,940 differed regarding their structures, CB receptor involvement, and death/fate responses and signaling. Safety and antitumor efficacy studies in animal models are warranted to guide further R&D.