Abstract

The search for novel anticancer small molecules and strategies remains a challenge. Our previous studies have identified TXA1 (1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H- thioxanthen-9-one) as a hit compound, with in vitro antitumor potential by modulating autophagy and apoptosis in human tumor cell lines. In the present study, the mechanism of action and antitumor potential of the soluble salt of this molecule (TXA1.HCl) was further investigated using in vitro and mouse xenograft tumor models of NSCLC. Our results showed that TXA1.HCl affected steroid biosynthesis, increased RagD expression, and caused abnormal cellular cholesterol localization. In addition, TXA1.HCl treatment presented no toxicity to nude mice and significantly reduced the growth of human NSCLC cells xenografts in mice. Overall, this work provides new insights into the mechanism of action of TXA1, which may be relevant for the development of anticancer therapeutic strategies, which target cholesterol transport.

Details

Title
The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization
Author
Lima, Raquel T 1   VIAFID ORCID Logo  ; Sousa, Diana 2 ; Gomes, Ana Sara 3   VIAFID ORCID Logo  ; Mendes, Nuno 4   VIAFID ORCID Logo  ; Matthiesen, Rune 5 ; Madalena Pedro 6 ; Marques, Franklim 7 ; Pinto, Madalena M 8   VIAFID ORCID Logo  ; Sousa, Emília 8   VIAFID ORCID Logo  ; Vasconcelos, M Helena 2   VIAFID ORCID Logo 

1  i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Cancer Drug Resistance Group—IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto; Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal 
2  i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Cancer Drug Resistance Group—IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto; Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal; Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal 
3  Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal 
4  i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; HEMS-Histology and Electron Microscopy-i3S, Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal 
5  Computational and Experimental Biology Group, The Chronic Diseases Research Center (CEDOC), Nova Medical School, Faculdade de Ciencias Medicas Universidade Nova De Lisboa, Rua Câmara Pestana 61150-082 Lisboa, Portugal 
6  CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, IUCS-Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal 
7  UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal 
8  Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP-Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR—Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal 
First page
3301
Publication year
2018
Publication date
2018
Publisher
MDPI AG
e-ISSN
14203049
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.3390/molecules23123301
ProQuest document ID
2582832803
Copyright
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.