Comparison of the Anticancer Effects of Arvanil and Olvanil When Combined with Cisplatin and Mitoxantrone in Various Melanoma Cell Lines—An Isobolographic Analysis

Abstract

Due to the unique structures of arvanil and olvanil, the drugs combine certain properties of both cannabinoids and vanilloids, which makes them able to stimulate both TPRV1 and CB1 receptors and causes them to be interesting agents in the setting of carcinoma treatment. The aim of this study was to investigate the cytotoxic and anti-proliferative effects of arvanil and olvanil when administered alone and in combination with cisplatin (CDDP) and mitoxantrone (MTX), using various primary (A375, FM55P) and metastatic (SK–MEL 28, FM55M2) human malignant melanoma cell lines. The results indicate that both arvanil and olvanil inhibited (dose-dependently) the viability and proliferation of various malignant melanoma cells, as demonstrated by MTT and BrdU assays. The safety profile of both arvanil and olvanil tested in human keratinocytes (HaCaT) and normal human melanocytes (HEMa–LP) revealed that neither arvanil nor olvanil caused significant cytotoxicity in HaCaT and HEMa–LP cell lines in LDH and MTT assays. Isobolographically, it was found that both arvanil and olvanil exerted additive interactions with MTX and antagonistic interactions with CDDP in the studied malignant melanoma cell lines. In conclusion, the combinations of arvanil or olvanil with MTX may be considered as a part of melanoma multi-drug therapy; however, the combination of these compounds with CDDP should be carefully considered due to the antagonistic interactions observed in the studied malignant melanoma cell lines.

Functional Selectivity of Cannabinoid Type 1 G Protein-Coupled Receptor Agonists in Transactivating Glycosylated Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition Metastatic Phenotype

“…The CB1 agonists, N-arachidonoyl aminophenol (AM 404) (KI: 2.57 μg/mL) [ 34 ], Arvanil (KI: 1.28 μg/mL) [ 35 ], and Olvanil (KI: 4.127 μg/mL) [ 35 ], were purchased from Alomone Labs, Jerusalem BioPark (JBP) (Jerusalem, Israel) and utilized in a dose-dependent manner. The KI value was used to create the dose–response curve.…”

AM1172 (a hydrolysis-resistant endocannabinoid analog that inhibits anandamide cellular uptake) reduces the viability of the various melanoma cells, but it exerts significant cytotoxic effects on healthy cells: an in vitro study based on isobolographic analysis

“…The HaCaT cell line – normal human keratinocyte cells (density: 1 × 10 4 cells/mL), HEMa-LP cell line – normal human melanocytes (density: 5 × 10 3 cells/mL) and four human malignant melanoma lines (A375, SK-MEL 28, FM55M2, FM55P) (density: 2–3 × 10 4 cells/mL, depending on the cell line) were plated on microtiter plates (NEST Biotechnology, Wuxi, China) The next day, the culture medium was removed and cells were exposed to serial dilutions of PACX, DOCX, AM1172, CDDP and MTX in a fresh culture medium. Cell viability was assessed after 72 h using the MTT test, as described earlier [ 26 ]. Each treatment was performed in triplicate and each experiment was repeated 3 times to ensure repeatability and validity of the results.…”

“…Data about the cytotoxicity was obtained by measuring cytoplasmic lactate dehydrogenase (LDH) activity released from the damaged cells after exposure. LDH assay was performed according to the manufacturer’s instruction (Cytotoxicity Detection KitPLUS LDH) (Roche Diagnostics, Mannheim, Germany), as described earlier [ 22 , 26 , 56 ].…”

“…In a xenograft mouse model, both CBD and Δ 9 THC (in a fixed ratio of 1:1) substantially inhibited viability, proliferation, and tumor growth in CHL-1 melanoma cells [ 25 ]. Similarly, arvanil and olvanil (two synthetic ligands for TRPV1 and CB1 receptors) reduced cell viability in different human malignant melanoma cell lines (A375, SK-MEL 28, FM55P, and FM55M2) [ 26 ]. Additionally, it has been reported that N -arachidonoyl-ethanolamine, also known as anandamide (AEA – an endogenous cannabinoid) produced cytotoxicity in A375 melanoma cells, which was enhanced by the inhibition of fatty acid amide hydrolase (FAAH), an enzyme degrading AEA [ 27 ].…”

“…Previously, it has been documented that CBD, arvanil, and olvanil inhibited cell proliferation in various human malignant melanoma cell lines (A375, FM55P, SK-MEL 28 and FM55M2) [ 22 , 26 ]. We sought therefore to continue our previous studies by assessing the antiproliferative potential of AM1172 (another compound that affects the endocannabinoid system) to shed more light on the antiproliferative effects of cannabinoid ligands in various malignant melanoma cell lines.…”