AUTHOR=Reis Mariana Alves , Matos Ana M. , Duarte Noélia , Ahmed Omar Bauomy , Ferreira Ricardo J. , Lage Hermann , Ferreira Maria-José U. 

TITLE=Epoxylathyrane Derivatives as MDR-Selective Compounds for Disabling Multidrug Resistance in Cancer

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00599

DOI=10.3389/fphar.2020.00599

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>Multidrug resistance (MDR) has been regarded as one of the major hurdles for the successful outcome of cancer chemotherapy. The collateral sensitivity (CS) effect is one the most auspicious anti-MDR strategies. Epoxylathyrane derivatives <bold>1–16</bold> were obtained by derivatization of the macrocyclic diterpene epoxyboetirane A (<bold>17</bold>), a lathyrane-type macrocyclic diterpene isolated from <italic>Euphorbia boetica</italic>. Some of these compounds were found to strongly modulate P-glycoprotein (P-gp/ABCB1) efflux.</p></sec><sec><title>Purpose</title><p>The main goal was to develop lathyrane-type macrocyclic diterpenes with improved MDR-modifying activity, by targeting more than one anti-MDR mechanism.</p></sec><sec><title>Study design/methods</title><p>In this study, the potential CS effect of compounds <bold>1</bold>–<bold>16</bold> was evaluated against gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) human cancer cells and their drug-resistant counterparts, respectively selected against mitoxantrone (EPG85-257RNOV; EPP85-181RNOV; HT-RNOV) or daunorubicin (EPG85-257RDB; EPP85-181RDB; HT-RDB). The most promising compounds (<bold>8</bold>, <bold>15</bold>, and <bold>16</bold>) were investigated as apoptosis inducers, using the assays annexin V/PI and active caspase-3.</p></sec><sec><title>Results</title><p>The compounds were more effective against the resistant gastric cell lines, being the CS effect more significant in EPG85-257RDB cells. Taking together the IC<sub>50</sub> values and the CS effect, compounds <bold>8</bold>, <bold>15</bold>, and <bold>16</bold> exhibited the best results. Epoxyboetirane P (<bold>8</bold>), with the strongest MDR-selective antiproliferative activity against gastric carcinoma EPG85-257RDB cells (IC<sub>50</sub> of 0.72 µM), being 10-fold more active against this resistant subline than in sensitive gastric carcinoma cells. The CS effect elicited by compounds <bold>15</bold> and <bold>16</bold> appeared to be by inducing apoptosis <italic>via</italic> caspase-3 activation. Structure-activity relationships of the compounds were additionally obtained through regression models to clarify the structural determinants associated to the CS effect.</p></sec><sec><title>Conclusions</title><p>This study reinforces the importance of lathyrane-type diterpenes as lead molecules for the research of MDR-modifying agents.</p></sec>