Chemo-sensitizing activity of natural cadinanes from Heterotheca inuloides in human uterine sarcoma cells and their in silico interaction with ABC transporters

Sensitizing activities exerted by 3,4-dihydro-7-hydroxycadalene (1), rac-3,7-dihydroxy-3(4H)-isocadalen-4-one (4) and (1R,4R)-4H-1,2,3,4-tetrahydro-1-hydroxycadalen-15-oic acid (9), the major cadinanes isolated from Heterotheca inuloides, towards multidrug-resistant MES-SA/MX2 and parental MES-SA epithelial human uterine sarcoma cell lines were evaluated. We also evaluated the in silico interactions (expressed as ΔG_binding in kcal/mol) of cadinanes 1, 4 and 9 in an in vitro assay, and also tested several structurally related natural compounds with the multidrug resistance protein (MDR1, P-glycoprotein), human multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP) structures as pharmacological targets using AutoDock and AutoDock Vina. Compound 1 potentiated the cytotoxicity of doxorubicin and mitoxantrone drugs in resistant MES-SA/MX2 cells, compared to cells treated with each drug alone. Compound 1 could reverse the resistance to doxorubicin 12.44 fold at a concentration of 5 μM. It also re-sensitized cells to mitoxantrone 3.94 fold. Hence, compound 1 may be considered as a potential chemosensitizing agent to overcome multidrug resistance in cancer. The docking analysis suggested that there are interactions between cadinanes from H. inuloides and MDR1, MRP1, and BCRP proteins mainly through π-π interactions and hydrogen bonds.