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

• Published in: PloS one Vol. 14; no. 4; p. e0214610
• Main Authors: O’Flaherty, Linda, Shnyder, Steven D., Cooper, Patricia A., Cross, Stephen J., Wakefield, James G., Pardo, Olivier E., Seckl, Michael J., Tavaré, Jeremy M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.04.2019; Public Library of Science (PLoS)
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Biology and Life Sciences; Cancer research; Cancer treatment; Carboplatin; Carcinoma; Carcinoma, Non-Small-Cell Lung - drug therapy; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Chromosome Aberrations - drug effects; Chromosomes; Drug Synergism; Drug Therapy, Combination; Enzymes; Genetic research; Glycogen; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen synthesis; Humans; Lung cancer; Lung Neoplasms - drug therapy; Male; Medicine and Health Sciences; Mice; Mice, Nude; Non-small cell lung cancer; Novels; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Pemetrexed; Polysaccharides; Pyridines - pharmacology; Pyridines - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; RNA Interference; RNA, Small Interfering - metabolism; Small cell lung cancer; Tumors
• DOI: 10.1371/journal.pone.0214610
• ISSN: 1932-6203

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.