Abstract
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. NSCLC development and progression have recently been correlated with the heightened activation of histone deacetylases (HDACs) and PI3K/Akt signaling pathways. Targeted inhibition of these proteins is promising approach for the development of novel therapeutic strategies to treat patients with advanced NSCLC. For this reason, we combined a dual PI3K and mTOR inhibitor, BEZ235 with the HDAC inhibitor Trichostatin A (TSA), to determine their combined effects on human NSCLC. In this study, we initially discovered that co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of NSCLC cell proliferation and induction of apoptosis. The combination treatment also synergistically suppressed NSCLC migration, invasion and the NSCLC epithelial-mesenchymal transition (EMT) in vitro. The synergistic effect was also evidenced by declines in xenograft growth and metastasis rates and in ki-67 protein expression in vivo. Together, these results indicated that BEZ235 and TSA combination treatment significantly increased anti-tumor activities compared with BEZ235 and TSA alone, supporting a further evaluation of combination treatment for NSCLC.
Highlights
Lung cancer is one of the most commonly diagnosed cancers worldwide [1]
The isobologram analysis indicated that the combination treatment effect was highly synergistic in both A549 and H460 (CI=0.71) cells (Figure 1C-1D), where the synergy was higher in A549 than in H460 cells
A genetic profile of alterations in human Non-small-cell lung cancer (NSCLC) has shown that simultaneous increases in Phosphatidylinositol 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) pathway activity and in dysregulated histone deacetylases (HDACs) expression are common [30]
Summary
Lung cancer is one of the most commonly diagnosed cancers worldwide [1]. NSCLC is the major histological form of epithelial lung cancer, and it remains the principle cause of cancer-related death, accounting for more than one million deaths per year [2, 3]. EGFR-TKI based targeted therapy generates a dramatic response in patients with advanced EGFR-mutation positive NSCLC [5, 6]. Most current therapeutic approaches are limited by drug resistance and subsequent disease relapse, as evidenced by the median overall survival rate of 25.5 months [7, 8]. Increasing evidences has suggested that acquired drug resistance limits the long-term effectiveness of EGFR-TKIs. a new therapeutic strategy is necessary for NSCLC treatment
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