Anticancer activity of mansonone G derivatives against human non-small cell lung cancer: computational and mechanistic study

Abstract

Epidermal growth factor receptor (EGFR) and DNA topoisomerase II (Topo II) are the key molecular targets for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. In the present study, mansonone G (MG), a naturally occurring quinone-containing compound, and its semi-synthetic ether derivatives were subjected to theoretically and experimentally investigate the anticancer effects on EGFR/Topo II-mediated signaling pathways in NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) was more susceptible to H1975 mutant cells (IC50 of 4.21 μM) than A549 wild-type cells (IC50 of 8.54 μM). Importantly, MG3 was low toxic against normal fibroblast cells (IC50 of 21.16 μM). Western blotting and flow cytometric analyses revealed that MG3 induced a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. According to the computational calculations on MGs/Topo II complexes, we found that, among all studied MGs, an ester derivative MG14 exhibited the highest binding affinity toward Topo II ATPase domain. In addition, the binding of MG14 against Topo II induced the residues 147-151 to locate closer to ligand, resulting in a closed conformation. Additionally, the encapsulation of mansonones(s) into the hydrophobic inner cavity of beta-cyclodextrins (βCDs), especially 2,6-dimethy-βCD derivative, led to the enhancement of solubility, stability, enantioseparation, and anticancer activity of the uncomplexed mansonone(s).