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Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer

Research output: Contribution to journalArticle

Original languageEnglish
Article numbere0214610
Pages (from-to)e0214610
Number of pages7
JournalPLoS ONE
Volume14
Issue number4
DOIs
DateAccepted/In press - 17 Mar 2019
DatePublished (current) - 10 Apr 2019

Abstract

Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Public Library of Science at https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214610 . Please refer to any applicable terms of use of the publisher.

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