Abstract
Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related deaths
To evaluate the specific functional significance of HAT inhibition in human non-small cell lung cancer (NSCLC), we explored cell proliferation of nine commercially available established NSCLC cell lines exposed to increasing concentrations of CPTH6, a novel Gcn5 and pCAF HAT inhibitor [12]
In order to investigate whether CPTH6 inhibition of cell viability was associated with cell death in NSCLC cells, H1299 cells were treated with CPTH6 for 24h at concentrations ranging from 20 to 100μM, and cell survival was assessed
Summary
Lung cancer is the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases [1]. The disease control achieved with classical chemotherapy doublets in advanced or metastatic NSCLC is usually restricted to only a few months [2]. There is a need for development of novel agents that can be added to and improve the effect of traditional chemotherapy. With growing insight into molecular alterations in lung cancer, tremendous efforts have been made to identify new anticancer agents. Aberrant epigenetic regulation is a frequent event in NSCLC, and both altered www.impactjournals.com/oncotarget
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