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  Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status

Xiao, Z., Sperl, B., Ullrich, A., & Knyazev, P. (2014). Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. ONCOTARGET, 5(24), 12877-12890.

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 Creators:
Xiao, Zhiguang1, Author              
Sperl, Bianca1, Author              
Ullrich, Axel1, Author              
Knyazev, Pjotr1, Author              
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1Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              

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Free keywords: GROWTH-FACTOR RECEPTOR; LUNG-CANCER; SOMATIC MUTATIONS; EXPRESSION; RESISTANCE; GEFITINIB; APOPTOSISNSCLC; CSCs; combinatorial treatment; Metformin; Salinomycin;
 Abstract: The presence of cancer stem cells (CSCs) is linked to preexisting or acquired drug resistance and tumor relapse. Therefore, targeting both differentiated tumor cells and CSCs was suggested as an effective approach for non-small cell lung cancer (NSCLC) treatment. After screening of chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) or monoclonal antibody in combination with the putative stem cell killer Salinomycin (SAL), we found Metformin (METF), which modestly exerted a growth inhibitory effect on monolayer cells and alveospheres/CSCs of 5 NSCLC cell lines regardless of their EGFR, KRAS, EML4/ALK and LKB1 status, interacted synergistically with SAL to effectively promote cell death. Inhibition of EGFR (AKT, ERK1/2) and mTOR (p70 s6k) signaling with the combination of METF and SAL can be augmented beyond that achieved using each agent individually. Phospho-kinase assay further suggested the multiple roles of this combination in reducing oncogenic effects of modules, such as beta-catenin, Src family kinases (Src, Lyn, Yes), Chk-2 and FAK. Remarkably, significant reduction of sphere formation was seen under combinatorial treatment in all investigated NSCLC cell lines. In conclusion, METF in combination with SAL could be a promising treatment option for patients with advanced NSCLC irrespective of their EGFR, KRAS, EML4/ALK and LKB1 status.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000348038000028
 Degree: -

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Title: ONCOTARGET
Source Genre: Journal
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Publ. Info: 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA : IMPACT JOURNALS LLC
Pages: - Volume / Issue: 5 (24) Sequence Number: - Start / End Page: 12877 - 12890 Identifier: ISSN: 1949-2553