Bioactive neolignans in combination with doxorubicin enhances cytotoxic activity against human melanoma A375 cells

Malignant melanoma is a cancer of high aggressiveness and lethality, resulting from mutations in melanocytes, which in the most advanced stages of current therapy is ineffective. Because of this, therapeutic alternatives are necessary, aiming the induction of cytotoxic effects against tumor and, at the same time, are not aggressive to the patient's body. Recent studies suggest that, combination therapy of chemotherapeutic agents and one or more natural products may be alternatives to reduce the drug resistance and increase sensitivity and the effect of chemotherapeutics. Lignans and neolignans, due to their structural diversity and their pharmacological features, such as, antitumor, hepatoprotective, insecticidal, antifungal, antihypertensive, sedative and antioxidant activity, have been the target of many chemopharmacological studies. In this sense, this work aims to evaluate the cytotoxic activity of natural dehydrodieugenol B (1), isolated from twigs of Nectandra leucantha, and their analogous FS1 and FS2. Initially, analogous compounds were prepared from natural product 1, by hydrogenation and acetylation reactions. Subsequentlly, all compounds were tested isolated and in combination with doxorubicin, to determine the cytotoxic profile against human melanoma (A375) and human embryonic kidney (HEK-293) cell lines, in addition to the combination effects. Cytotoxicity of dehydrodieugenol B and derivatives were evaluated using the Fluorimetric Resazurin Assay, to quantify the cell viabilities. The compounds were tested over a concentration range of 0 – 100µM. Cells were treated for 72 h at 37°C and IC50 values were obtained from dose–effect curves using Prism 6.0 (GraphPad Software Inc). The isolated compound 1 and, prepared derivatives FS1 and FS2, respectively displayed IC50 values of 24.0, 15.8, 15.7µM in A375 cells, independently. Demonstrating that the hydrogenation and acetylation of 1 increase the antitumoral activity, when compared with dehydrodieugenol B. Besides that, the neolignans and doxorubicin association, at 1:1 ratio, improved the cytotoxic potentiaI, displaying IC50 values of 0.6, 0.73 and 0.32 µM, that were respectively attributed to the combination with 1, FS1 and FS2. Comparing IC50 values of doxorubicin alone and in combination with FS2 (FS2+Doxorubicin), against A375 and HEK-293 cell lines, the IC50 values for FS2+Doxorubicin was lower than doxorubicin alone (Table 1). Furthermore, combined compounds demonstrated better selectivity than the standard drug, highlighting that combination might be a promising approach to treat melanoma.