Antineoplastic Properties of THCV, HHC and their anti-Proliferative effects on HPAF-II, MIA-paca2, Aspc-1, and PANC-1 PDAC Pancreatic Cell Lines

Abstract

Cannabinoid receptors CB1 and CB2 are the primary endogenous receptors with which cannabinoids interact, inducing physiological and psychological effects. Although interactions with other receptors including TRPV1 and GPCR55, have been recognized in earlier studies, these interactions may play a significant role in cancer remediation through the unspecified upregulation or downregulation of specific pathways. The main active constituents within the cannabis plant are cannabidiol (CBD) and tetrahydrocannabinol (THC), which have been categorized as either non-intoxicating with benefit or intoxicating with no benefit. These categories are constantly ignored, as cannabinoids have shown efficacy in the treatment of certain diseases and ailments as single-agent compounds. Tetrahydrocannabivarin (THCV), a rare cannabinoid, is a homologue of THC, with the C5 alkyl chain having three carbons rather than the standard five carbon length. THCV has garnered attention in a clinical setting as an anti-obesity drug treating glucose issues. Hexahydrocannabinol (HHC), a hydrogenated analogue of THC, is a rare cannabinoid like THCV. These cyclic cannabinoids are considered rare, because they are typically found in minimal to trace amounts within cannabis sativa and their given C. indica, and C. ruderalis sub species. Increased popularity of these rare cannabinoids has led to proposed experimentation leading to assessing the cytotoxicity of these cannabinoids toward, cancer cells of the pancreas (MIA-PaCa2, HPAF-II, and PANC1). The data evaluated through such studies led to the proposed idea of these rare cyclic cannabinoids towards the treatment of pancreatic cancer due to the modest efficacy as single agent antineoplastics compared to common single agent antineoplastics on the market, with evidence being strongly presented when compared to commercially available anticancer agents poly(ADP-ribose) polymerase (PARP) inhibitors.

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

“…Both epimers Mixture of HHC epimers, also mixture of HHCV epimers Both epimers Both epimers EMCDDA 164 Stothard et al 158 Tesfatsion et al 76 Collins et al 91 Russo et al 96 13 C NMR spectroscopy 9β-HHC analog lacking side-chain 9β-HHC 9β-HHC Mixture of epimers Both epimers Mixture of HHC epimers Mixture of HHC epimers; also mixture of HHCV epimers Both epimers Both epimers Zetta et al 176 Wang et al 107 Lee 174 Seccamani et al 138 Casati et al 89 EMCDDA 164 Tesfatsion et al 76 Collins et al 91 Russo et al 96 Mass 177 Rosenthal et al 163 Harvey & Paton 178 Harvey 179 Cornia et al 46 Harvey & Brown 92 Harvey & Brown 93 Wang et al 107 Seccamani et al 138 NIST 180 Casati et al 89 Cayman Chemical 181,182 EMCDDA 164 Karin et al 171 Sams 155 Smith et al 165 Stothard et al 158 Collins et al 91 Radwan et al 135 Russo et al 96 Radioimmunoassay d 8α-hydroxy-HHC e Comparative study of three radioimmunoassays HPLC-radioimmunoassay HPLC-radioimmunoassay 9α/β-HHC, 11-nor-9α/β-carboxy-HHC (see Table 4) <40% cross-reactivity No cross reaction with HHC-O f Teale et al 184 Cook et al 185 Williams et al 166 Moffat et al 167 Jones ...…”

“…11 For the cyclization of the CBD homolog cannabidivarinol (CBDV), triisobutylaluminum has also been used. 76 The ratio of the two THC isomers as well as the amount and chemical nature of the byproducts depends on the reaction conditions. Under mild acidic conditions, Δ 9 -THC could be obtained in relatively high purity.…”

“…Visualization by KMnO 4 solution Gaoni and Mechoulam Tietze et al 43 Visualization by acidic anisaldehyde solution Casati et al 89 Visualization by ceric ammonium molybdate Stothard et al 158 Gas chromatography Includes hexahydrocannabivarinol and "abnormal" HHC Includes cis and trans "abnormal" HHCs Heptafluorobutyryl derivative GC-flame ionization GC-MS GC-MS; TMS b derivative GC-MS; TMS b derivative GC-MS; also TMS b derivatives GC-MS/MS; MSTFA c derivative EI, 71 eV; GC-MS; ESI; HPLC-MS/MS GC-MS GC-MS GC-MS GC-MS Vree et al 159 Vree et al 160 Fenimore et al 161 Waller et al 162 Rosenthal et al 163 Harvey and Brown 92 Harvey and Brown 93 Seccamani et al 138 Casati et al 89 EMCDDA 164 Sams 155 Smith et al 165 Stothard et al 158 Collins et al 91 High-performance liquid chromatography HPLC-radioimmunoassay HPLC-radioimmunoassay HPLC-electrochemical detection HPLC-photodiode array UV HPLC-photodiode array UV HPLC-MS/MS HPLC-MS/MS HPLC-MS Both epimers; baseline separation Mixture of HHC epimers; also mixture of HHCV epimers HPLC-photodiode array UV; both epimers HPLC-photodiode array UV; HPLC-MS; both epimers of H4CBD as well Williams et al 166 Moffat et al 167 Thompson and Cone 168 Hill et al 169 Colorado Chromatography 170 EMCDDA 164 Karin et al 171 Sams 155 Stothard et al 158 Tesfatsion et al 76 Collins et al 91 Russo et al 96…”

“…The cyclization can be affected by the use of ethanolic solution of hydrogen chloride or phosphoric acid, zinc chloride, sulfamic acid, or pyridine hydrochloride as catalyst 11 . For the cyclization of the CBD homolog cannabidivarinol (CBDV), triisobutylaluminum has also been used 76 . The ratio of the two THC isomers as well as the amount and chemical nature of the byproducts depends on the reaction conditions.…”

“…A recent preprint reported on preliminary results of the anticancer properties of the two HHC epimers in four pancreatic cancer cell lines 76 (Table 6). While data for Δ 9 ‐THC were not reported, both epimers of HHC similarly inhibited the proliferation of cancer cells with IC 50 values ranging from 10.3 to 27.2 μM; these values were comparable to the IC 50 values of the anticancer agents olaparib or veliparib.…”