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.