Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations

Abstract

Epidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-containing compound, and its semi-synthetic ether derivatives were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC50 of 8.54 μM) and H1975 (IC50 of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC50 of 21.16 μM). Western blotting and flow cytometric analyses revealed that MG3 induces 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. The 500-ns molecular dynamics simulations and the molecular mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calculations suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component analysis, the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, especially the residues in the active site, stabilizing MG3 mainly through van der Waals interactions.

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

“…In addition, coimmunoprecipitation assay indicated that genipin inhibited STAT-1:STAT-3 heterodimerization and STAT-3: STAT-3 homodimerization. In previous research, Mahalapbutr et al found that the SH2 domain was critical for EGFR and STAT-3 interaction and subsequent STAT-3: STAT-3 homodimerization [39]. In our study, it was revealed that genipin could suppress EGFR-STAT-3 interaction and further inhibit STAT-3 dimerization.…”

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

“…In previous research, Mahalapbutr, P et. al found that SH2 domain was critical for EGFR and STAT-3 interaction and subsequent STAT-3:STAT-3 homodimerization [34]. In our study, we revealed that genipin could suppress EGFR-STAT-3 interaction and further inhibit STAT-3 dimerization.…”

Enhanced Solubility and Anticancer Potential of Mansonone G By β-Cyclodextrin-Based Host-Guest Complexation: A Computational and Experimental Study

“…Many lines of evidence have shown that MG exhibits a potent anticarcinogenic effect on various types of malignancies, e.g., ovarian (A278, IC 50 of 10.2 μM), colorectal (HCT116, IC 50 of 63.4 µM), liver (HepG2, IC 50 of 36.3 µM and Huh-7, IC 50 of 25.9 µM), breast (MCF-7, IC 50 of 23.0 µM), and cervical (HeLa, IC 50 of 18.8 µM) cancer cell lines [5,12,13], and it has been documented to significantly inhibit the activity of P-glycoprotein efflux pump [5]. Recently, the butoxy MG has shown to potentially induce cell apoptosis in human lung cancer cell lines A549 and H1975 by inhibiting STAT3 and Akt signaling pathways [14]. Even though MG could serve as a promising anticancer agent, its poor water solubility (1.7 mg/L at 30 °C) leads to a limited use for pharmaceutical and medicinal applications.…”