Olvanil

Glioblastoma is the most aggressive malignant brain tumor characterized by rapid development, poor prognosis and high mortality. The purpose of this in vitro study was to assess cytotoxic and anti-proliferative effects of arvanil, olvanil and LY2183240 (three cannabinoid receptor ligands), when used alone and in combination with cisplatin and temozolomide in various neuroblastoma (CHP-134 and KELLY) and glioblastoma (U87MG, C6, and T98G) cell lines in the MTT assay. Results indicate that arvanil, olvanil and LY2183240 considerably affected the viability of neuroblastoma and glioblastoma cell lines with selectivity index values ranging from 0.50 to 17.48 for arvanil; from 0.93 to 24.06 for olvanil; and from 1.68 to 14.52 for LY2183240. With isobolographic analysis we found that the combination of LY2183240 with cisplatin produced three different types of interactions: a synergy in CHP-134; an antagonism in T98G; and additivity in KELLY, C6 and U87MG cell lines in the MTT assay. The combinations of arvanil and olvanil with cisplatin exerted additive interaction in all the tested cell lines in the MTT assay. Similarly, the combinations of temozolomide with arvanil, olvanil and LY 2183240 produced the additive interaction in all the tested glioblastoma and neuroblastoma cell lines. In conclusion, the combinations of temozolomide with the three cannabinoids, due to their additive interactions, can be considered as a promising therapeutic direction in glioblastoma. Favorable combinations of cisplatin with arvanil, olvanil and LY2183240 can also be recommended, except for a combination of cisplatin with LY2183240 in glioblastoma T98G cell line in the MTT assay.

Glioblastoma is one of the most lethal tumors, displaying striking cellular heterogeneity and drug resistance. The prognosis of patients suffering from glioblastoma after 5 years is only 5%. In the present work, capsaicin analogues bearing modifications on the acyl chain with long-chain fatty acids showed promising anti-tumoral activity by its cytotoxicity on U-87 and U-138 glioblastoma multiforme cells. The capsaicin analogues were enzymatically synthetized with cross-linked enzyme aggregates of lipase B from Candida antarctica (CALB). The catalytic performance of recombinant CALB-CLEAs was compared to their immobilized form on a hydrophobic support. After 72 h of reaction, the synthesis of capsaicin analogues from linoleic acid, docosahexaenoic acid, and punicic acid achieved a maximum conversion of 69.7, 8.3 and 30.3% with CALB-CLEAs, respectively. Similar values were obtained with commercial CALB, with conversion yields of 58.3, 24.2 and 22% for capsaicin analogues from linoleic acid, DHA and punicic acid, respectively. Olvanil and dohevanil had a significant cytotoxic effect on both U-87 and U-138 glioblastoma cells. Irrespective of the immobilization form, CALB is an efficient biocatalyst for the synthesis of anti-tumoral capsaicin derivatives.

• This is the first report concerning the enzymatic synthesis of capsaicin analogues from docosahexaenoic acid and punicic acid with CALB-CLEAs.• The viability U-87 and U-138 glioblastoma cells was significantly affected after incubation with olvanil and dohevanil.• Capsaicin analogues from fatty acids obtained by CALB-CLEAs are promising candidates for therapeutic use as cytotoxic agents in glioblastoma cancer cells.