title: 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.
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Marta
authors: M
authors: Di Martile
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Marianna
authors: M
authors: Desideri
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Teresa
authors: T
authors: De Luca
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Chiara
authors: C
authors: Gabellini
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Simonetta
authors: S
authors: Buglioni
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Adriana
authors: A
authors: Eramo
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Giovanni
authors: G
authors: Sette
authors: Clinical and Experimental Oncology Department, Regina Elena National Cancer Institute, Rome, Italy.
authors: Michele
authors: M
authors: Milella
authors: Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy.
authors: Dante
authors: D
authors: Rotili
authors: Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy.|Pasteur Institute, Cenci Bolognetti Foundation, 'Sapienza' University, Rome, Italy.
authors: Antonello
authors: A
authors: Mai
authors: Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy.
authors: Simone
authors: S
authors: Carradori
authors: Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy.
authors: Daniela
authors: D
authors: Secci
authors: Scientific Director, Regina Elena National Cancer Institute, Rome, Italy.
authors: Ruggero
authors: R
authors: De Maria
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Donatella
authors: D
authors: Del Bufalo
authors: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors: Daniela
authors: D
authors: Trisciuoglio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C573972:3-methylcyclopentylidene-(4-(4'-chlorophenyl)thiazol-2-yl)hydrazone; D000970:Antineoplastic Agents; D013844:Thiazoles; D051548:Histone Acetyltransferases
keywords: HAT inhibitors; acetylation; apoptosis; cancer stem cells; non-small cell lung cancer