Abstract
By screening a collection of one hundred combinations of thiazolidinone compounds, we identified one combination (M4) that synergistically inhibited the growth of H460 and H460/TaxR cells and tumor growth in H460/TaxR xenograft mice. A whole genome microarray assay showed that genes involved in negative regulation of microtubule polymerization or depolymerization, intracellular protein kinase cascade, positive regulation of histone acetylation, cell cycle arrest and apoptosis were upregulated. Further analysis proved that the four compounds act as either microtubule polymerization inhibitors or histone deacetylase inhibitors. They act synergistically targeting multiple proteins and leading to the regulation of cell cycle checkpoint proteins, including p53, p21, cdc25C and cdc2, the activation of caspases, JNK, p38 cascades and the inactivation of Akt. These events resulted in the G2/M cell cycle arrest and cell apoptosis. These data provide a new strategy for discovering anticancer drugs and drug combinations for drug-resistant cancers.
Highlights
Discovery of single target-specific drugs has been the focus of cancer drug development
To test whether individual compounds or M4 is the substrate or the inhibitor of the P-gp, we investigated the cancer cell growth inhibition in the presence of the P-gp inhibitor and the accumulation of rhodamine 123 (Rho 123) in H460/TaxR cells under the treatment of individual compounds or M4
The results showed that P-gp inhibition did not affect the concentration of drug to cause 50% inhibition of growth (GI50) values of the four compounds or M4 in H460/TaxR cells obviously, whereas the GI50 value of paclitaxel was decreased 18-fold (Table 1)
Summary
Discovery of single target-specific drugs has been the focus of cancer drug development. Multi-level and multi-targeting therapies[14,15] have shown potential applications in cancer treatment Such therapies, including multi-component drugs or multi-targeting drugs, may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive the growth of tumors. Received 24.10.13; revised 29.1.14; accepted 30.1.14; Edited by A Stephanou property and minimal side effects.[13,25] Some of these compounds inhibit tubulin polymerization, cause cell cycle arrest and induce apoptosis. They target various kinases depending on their chemical structures. To the best of our knowledge, this is the first work that reports the synergistic anticancer activity of structured agents by targeting tubulin depolymerization and HDAC simultaneously
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