Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

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.

Inhibition of lysine acetyltransferases impairs tumor angiogenesis acting on both endothelial and tumor cells

“…Of note, CPTH6 induced a remarkable reduction of the cytosolic protein α-tubulin acetylation at K40 residue in HUVEC ( Fig. 2a) as previously demonstrated in cancer cell lines [17][18][19]. These data were confirmed by immunostaining of acetylated and tyrosinated α-tubulin forms, the latter was used as a control.…”

“…In vivo angiogenesis matrigel assay was performed as previously reported [21]. Tumor vascularization of LCSC136 xenografts after treatment with CPTH6 [17] was evaluated by detecting CD31-positive cells in 5 μm paraffin sections by a streptavidin-biotin enhanced immunoperoxidase technique in an automated autostainer (BondTM Max, Leica BioSystem). For each tumor, three different 5 μm sections were analyzed and examined by light microscopy.…”

“…In order to study the possible effect on angiogenesis of CPTH6, a thiazole derivative inducing HAT inhibition [17,19], we performed matrigel plug angiogenesis assay in mice. As shown in Fig.…”

“…Moreover, reduction of HAT GCN5 represses bone marrow stromal cells-mediated angiogenesis [16]. In order to explore the hypothesis that HATs may provide key therapeutic targets for manipulation of angiogenic responses and new clues for anti-angiogenesis therapies, we investigated the effect of the HAT inhibitor 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6) [17][18][19] on both ECs and cancer cells by using in vitro and in vivo functional assays.…”

O papel da quinase Aurora A na biologia das células iniciadoras de turmor pulmonares com mutação em <i>KRAS</i>

“…Portanto, as diferenças funcionais entre células com e sem potencial tumorigênico têm implicações importantes para terapia. De fato, terapias dirigidas a CITs se mostraram benéficas em câncer de pâncreas (Jimeno et al, 2009;Li et al, 2011;Balic et al, 2014) e de pulmão (Sullivan et al, 2010;Serrano et al, 2011;Jokinen et al, 2014;Yang et al, 2015;Di martile et al, 2016;Liu et al, 2016).…”