Cargando…

Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway

BACKGROUND: Compound with cancer stem cell (CSC)-suppressing activity is promising for the improvement of lung cancer clinical outcomes. Toward this goal, we discovered the CSC-targeting activity of resveratrol (RES) analog moscatilin (MOS). With slight structural modification from RES, MOS shows do...

Descripción completa

Detalles Bibliográficos
Autores principales: Thongsom, Sunisa, Racha, Satapat, Petsri, Korrakod, Ei, Zin Zin, Visuttijai, Kittichate, Moriue, Sohsuke, Yokoya, Masashi, Chanvorachote, Pithi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239606/
https://www.ncbi.nlm.nih.gov/pubmed/37270520
http://dx.doi.org/10.1186/s12906-023-04016-6
_version_ 1785053523572948992
author Thongsom, Sunisa
Racha, Satapat
Petsri, Korrakod
Ei, Zin Zin
Visuttijai, Kittichate
Moriue, Sohsuke
Yokoya, Masashi
Chanvorachote, Pithi
author_facet Thongsom, Sunisa
Racha, Satapat
Petsri, Korrakod
Ei, Zin Zin
Visuttijai, Kittichate
Moriue, Sohsuke
Yokoya, Masashi
Chanvorachote, Pithi
author_sort Thongsom, Sunisa
collection PubMed
description BACKGROUND: Compound with cancer stem cell (CSC)-suppressing activity is promising for the improvement of lung cancer clinical outcomes. Toward this goal, we discovered the CSC-targeting activity of resveratrol (RES) analog moscatilin (MOS). With slight structural modification from RES, MOS shows dominant cytotoxicity and CSC-suppressive effect. METHODS: Three human lung cancer cell lines, namely H23, H292, and A549, were used to compare the effects of RES and MOS. Cell viability and apoptosis were determined by the MTT assay and Hoechst33342/PI double staining. Anti-proliferative activity was determined by colony formation assay and cell cycle analysis. Intracellular reactive oxygen species (ROS) were measured by fluorescence microscopy using DCFH(2)-DA staining. CSC-rich populations of A549 cells were generated, and CSC markers, and Akt signaling were determined by Western blot analysis and immunofluorescence. Molecular docking and molecular dynamics (MD) simulations were used to predict the possible binding of the compound to Akt protein. RESULTS: In this study, we evaluated the effects of RES and MOS on lung cancer and its anti-CSC potential. Compared with RES, its analog MOS more effectively inhibited cell viability, colony formation, and induced apoptosis in all lung cancer cell lines (H23, H292, and A549). We further investigated the anti-CSC effects on A549 CSC-rich populations and cancer adherent cells (A549 and H23). MOS possesses the ability to suppress CSC-like phenotype of lung cancer cells more potent than RES. Both MOS and RES repressed lung CSCs by inhibiting the viability, proliferation, and lung CSC-related marker CD133. However, only MOS inhibits the CSC marker CD133 in both CSC-rich population and adherent cells. Mechanistically, MOS exerted its anti-CSC effects by inhibiting Akt and consequently restored the activation of glycogen synthase kinase 3β (GSK-3β) and decreased the pluripotent transcription factors (Sox2 and c-Myc). Thus, MOS inhibits CSC-like properties through the repression of the Akt/GSK-3β/c-Myc pathway. Moreover, the superior inhibitory effects of MOS compared to RES were associated with the improved activation of various mechanism, such as cell cycle arrest at G2/M phase, production of ROS-mediated apoptosis, and inhibition of Akt activation. Notably, the computational analysis confirmed the strong interaction between MOS and Akt protein. MD simulations revealed that the binding between MOS and Akt1 was more stable than RES, with MM/GBSA binding free energy of − 32.8245 kcal/mol at its allosteric site. In addition, MOS interacts with Trp80 and Tyr272, which was a key residue in allosteric inhibitor binding and can potentially alter Akt activity. CONCLUSIONS: Knowledge about the effect of MOS as a CSC-targeting compound and its interaction with Akt is important for the development of drugs for the treatment of CSC-driven cancer including lung cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-023-04016-6.
format Online
Article
Text
id pubmed-10239606
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-102396062023-06-05 Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway Thongsom, Sunisa Racha, Satapat Petsri, Korrakod Ei, Zin Zin Visuttijai, Kittichate Moriue, Sohsuke Yokoya, Masashi Chanvorachote, Pithi BMC Complement Med Ther Research BACKGROUND: Compound with cancer stem cell (CSC)-suppressing activity is promising for the improvement of lung cancer clinical outcomes. Toward this goal, we discovered the CSC-targeting activity of resveratrol (RES) analog moscatilin (MOS). With slight structural modification from RES, MOS shows dominant cytotoxicity and CSC-suppressive effect. METHODS: Three human lung cancer cell lines, namely H23, H292, and A549, were used to compare the effects of RES and MOS. Cell viability and apoptosis were determined by the MTT assay and Hoechst33342/PI double staining. Anti-proliferative activity was determined by colony formation assay and cell cycle analysis. Intracellular reactive oxygen species (ROS) were measured by fluorescence microscopy using DCFH(2)-DA staining. CSC-rich populations of A549 cells were generated, and CSC markers, and Akt signaling were determined by Western blot analysis and immunofluorescence. Molecular docking and molecular dynamics (MD) simulations were used to predict the possible binding of the compound to Akt protein. RESULTS: In this study, we evaluated the effects of RES and MOS on lung cancer and its anti-CSC potential. Compared with RES, its analog MOS more effectively inhibited cell viability, colony formation, and induced apoptosis in all lung cancer cell lines (H23, H292, and A549). We further investigated the anti-CSC effects on A549 CSC-rich populations and cancer adherent cells (A549 and H23). MOS possesses the ability to suppress CSC-like phenotype of lung cancer cells more potent than RES. Both MOS and RES repressed lung CSCs by inhibiting the viability, proliferation, and lung CSC-related marker CD133. However, only MOS inhibits the CSC marker CD133 in both CSC-rich population and adherent cells. Mechanistically, MOS exerted its anti-CSC effects by inhibiting Akt and consequently restored the activation of glycogen synthase kinase 3β (GSK-3β) and decreased the pluripotent transcription factors (Sox2 and c-Myc). Thus, MOS inhibits CSC-like properties through the repression of the Akt/GSK-3β/c-Myc pathway. Moreover, the superior inhibitory effects of MOS compared to RES were associated with the improved activation of various mechanism, such as cell cycle arrest at G2/M phase, production of ROS-mediated apoptosis, and inhibition of Akt activation. Notably, the computational analysis confirmed the strong interaction between MOS and Akt protein. MD simulations revealed that the binding between MOS and Akt1 was more stable than RES, with MM/GBSA binding free energy of − 32.8245 kcal/mol at its allosteric site. In addition, MOS interacts with Trp80 and Tyr272, which was a key residue in allosteric inhibitor binding and can potentially alter Akt activity. CONCLUSIONS: Knowledge about the effect of MOS as a CSC-targeting compound and its interaction with Akt is important for the development of drugs for the treatment of CSC-driven cancer including lung cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-023-04016-6. BioMed Central 2023-06-03 /pmc/articles/PMC10239606/ /pubmed/37270520 http://dx.doi.org/10.1186/s12906-023-04016-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Thongsom, Sunisa
Racha, Satapat
Petsri, Korrakod
Ei, Zin Zin
Visuttijai, Kittichate
Moriue, Sohsuke
Yokoya, Masashi
Chanvorachote, Pithi
Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
title Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
title_full Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
title_fullStr Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
title_full_unstemmed Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
title_short Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
title_sort structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of akt signaling pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239606/
https://www.ncbi.nlm.nih.gov/pubmed/37270520
http://dx.doi.org/10.1186/s12906-023-04016-6
work_keys_str_mv AT thongsomsunisa structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT rachasatapat structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT petsrikorrakod structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT eizinzin structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT visuttijaikittichate structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT moriuesohsuke structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT yokoyamasashi structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway
AT chanvorachotepithi structuralmodificationofresveratrolanalogueexhibitsanticanceractivityagainstlungcancerstemcellsviasuppressionofaktsignalingpathway