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Open AccessArticle

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

1
Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
2
Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
3
Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
4
Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(4), 437; https://doi.org/10.3390/cancers11040437
Received: 11 January 2019 / Revised: 22 March 2019 / Accepted: 25 March 2019 / Published: 28 March 2019
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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. View Full-Text
Keywords: non-small cell lung cancer; mansonone G; apoptosis; STAT3; Akt; molecular dynamics simulation non-small cell lung cancer; mansonone G; apoptosis; STAT3; Akt; molecular dynamics simulation
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MDPI and ACS Style

Mahalapbutr, P.; Wonganan, P.; Chavasiri, W.; Rungrotmongkol, T. Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations. Cancers 2019, 11, 437. https://doi.org/10.3390/cancers11040437

AMA Style

Mahalapbutr P, Wonganan P, Chavasiri W, Rungrotmongkol T. Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations. Cancers. 2019; 11(4):437. https://doi.org/10.3390/cancers11040437

Chicago/Turabian Style

Mahalapbutr, Panupong; Wonganan, Piyanuch; Chavasiri, Warinthorn; Rungrotmongkol, Thanyada. 2019. "Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations" Cancers 11, no. 4: 437. https://doi.org/10.3390/cancers11040437

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