Frangula alnus ekstrakt i emodin kao potencijalni antikancerski agensi

Abstract

Hepatocelularni i kolorektalni karcinom se sve ćešće javlja i ima visoku stopu smrtnosti. Postojanje aktivnih mehanizama hemorezistencije otežava korisnost hemoterapije. Upravo je pojava hemorezistencije podstakla opsežna istraživanja za razvoj novih terapeutskih agenasa i strategija za lečenje ovih vrsta karcinoma. Prirodni proizvodi biljnog porekla (sekundarni metaboliti) su bogat izvor potencijalnih lekova. Zbog toga smo u istraživanju usmerili pažnju na etil-acetatni ekstrakt biljke Frangula alnus (FA) i njegovu dominantnu komponentu emodin (E) i ispitali njihovo antikancerski potencijal na ćelijama hepatocelularnog (HepG2) i kolorektalnog (HCT116) karcinoma i citotoksičnost na normalnim MRC -5 ćelijama. Pokazan je snažan antioksidativni potencijal ekstrakta (DPPH i TBA test). Citotoksičnost ispitana MTT testom pokazala je jaku toksičnost obe supstance na ćelije HepG2 i HCT116, ali bez uticaja na MRC-5 ćelije. Dalje je analiza ćelijskog ciklusa pokazala da su i FA i E izazvali zaustavljanje u G1 fazi i blago nakupljanje ćelija u G2/M fazi. Pored toga, obe supstance su uvele ćelije u apoptozu i nekrozu i uticale su na mitohondrijalni membranski potencijal. Dalje, izazvali su značajan genotoksični efekat u kometnom testu na svim ćelijskim linijama. Može se zaključiti da su FA i E dobri kandidati za nove antikancerogene agense prirodnog porekla. Međutim, neophodna su dodatna istraživanja, posebno kada je u pitanju citotoksična aktivnost i bezbednost primene ovih supstanci.

Hepatocellular and colorectal carcinoma is swiftly increasing alongside a high mortality rate. The existence of active mechanisms of chemoresistance hampers the usefulness of chemotherapy. The emergence of chemoresistance encouraged extensive research to develop new therapeutic agents and strategies for the treatment of these types of cancer. Natural products of plant origin (secondary metabolites) have been the most successful source of potential drug leads. Therefore, we turned our attention to the Frangula alnus ethyl-acetate extract (FA) and its dominant constituent emodin (E) and explored them for their anticancer potential on hepatocellular (HepG2) and colorectal (HCT116) carcinoma cells, and cytotoxicity on normal MRC-5 cells. Strong antioxidant potential of the extract was demonstrated (DPPH and TBA test). Cytotoxicity investigated by the MTT assay showed strong cell toxicity of both substances on HepG2 and HCT116 cells, but without affecting MRC-5 cells. Next, the analysis of cell cycles exhibited that both FA and E induced arrest in the G1 phase and slight accumulation of cells in the G2/M phase. In addition, both substances introduced cells into apoptosis and necrosis and modulated mitochondrial membrane potential. Further on, they caused significant genotoxic effect in comet assay applied in all cell lines. It can be concluded that FA and E are good candidates for new anticancer agents of natural origin. However, additional studies are necessary, especially when it comes to the cytotoxic activity and safety of the application of these substances.