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Molecules. 2018 Dec 12;23(12). pii: E3301. doi: 10.3390/molecules23123301.

The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization.

Lima RT1,2,3, Sousa D4,5,6, Gomes AS7,8, Mendes N9,10, Matthiesen R11, Pedro M12, Marques F13, Pinto MM14,15, Sousa E16,17, Vasconcelos MH18,19,20.

Author information

1
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. rlima@ipatimup.pt.
2
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. rlima@ipatimup.pt.
3
Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal. rlima@ipatimup.pt.
4
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. dsousa@ipatimup.pt.
5
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. dsousa@ipatimup.pt.
6
Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. dsousa@ipatimup.pt.
7
Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. anasarag4@gmail.com.
8
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. anasarag4@gmail.com.
9
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. nmendes@ipatimup.pt.
10
HEMS-Histology and Electron Microscopy-i3S, Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal. nmendes@ipatimup.pt.
11
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. rune.matthiesen@nms.unl.pt.
12
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. madalena.oliveira.pedro@gmail.com.
13
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. franklim@ff.up.pt.
14
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. madalena@ff.up.pt.
15
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. madalena@ff.up.pt.
16
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. esousa@ff.up.pt.
17
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. esousa@ff.up.pt.
18
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. hvasconcelos@ipatimup.pt.
19
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. hvasconcelos@ipatimup.pt.
20
Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. hvasconcelos@ipatimup.pt.

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.

KEYWORDS:

antitumor activity; cholesterol localization; non-small cell lung cancer; rags; thioxanthones; tumor xenografts

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