The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization

Raquel T. Lima, Diana Sousa, Ana Sara Gomes, Nuno Mendes, Rune Matthiesen, Madalena Pedro, Franklim Marques, Madalena M. Pinto, Emília Sousa, M. Helena Vasconcelos

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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.

Original languageEnglish
Article number3301
JournalMolecules
Volume23
Issue number12
DOIs
Publication statusPublished - 12 Dec 2018

Fingerprint

cholesterol
Heterografts
mice
Tumors
Cholesterol
Molecules
Biosynthesis
Autophagy
tumors
Tumor Cell Line
Nude Mice
Action Potentials
Toxicity
steroids
biosynthesis
Salts
Steroids
Cells
apoptosis
Apoptosis

Keywords

  • Antitumor activity
  • Cholesterol localization
  • Non-small cell lung cancer
  • Rags
  • Thioxanthones
  • Tumor xenografts

Cite this

Lima, R. T., Sousa, D., Gomes, A. S., Mendes, N., Matthiesen, R., Pedro, M., ... Helena Vasconcelos, M. (2018). The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization. Molecules, 23(12), [3301]. https://doi.org/10.3390/molecules23123301
Lima, Raquel T. ; Sousa, Diana ; Gomes, Ana Sara ; Mendes, Nuno ; Matthiesen, Rune ; Pedro, Madalena ; Marques, Franklim ; Pinto, Madalena M. ; Sousa, Emília ; Helena Vasconcelos, M. / The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization. In: Molecules. 2018 ; Vol. 23, No. 12.
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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",
author = "Lima, {Raquel T.} and Diana Sousa and Gomes, {Ana Sara} and Nuno Mendes and Rune Matthiesen and Madalena Pedro and Franklim Marques and Pinto, {Madalena M.} and Em{\'i}lia Sousa and {Helena Vasconcelos}, M.",
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Lima, RT, Sousa, D, Gomes, AS, Mendes, N, Matthiesen, R, Pedro, M, Marques, F, Pinto, MM, Sousa, E & Helena Vasconcelos, M 2018, 'The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization', Molecules, vol. 23, no. 12, 3301. https://doi.org/10.3390/molecules23123301

The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization. / Lima, Raquel T.; Sousa, Diana; Gomes, Ana Sara; Mendes, Nuno; Matthiesen, Rune; Pedro, Madalena; Marques, Franklim; Pinto, Madalena M.; Sousa, Emília; Helena Vasconcelos, M.

In: Molecules, Vol. 23, No. 12, 3301, 12.12.2018.

Research output: Contribution to journalArticle

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T1 - The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization

AU - Lima, Raquel T.

AU - Sousa, Diana

AU - Gomes, Ana Sara

AU - Mendes, Nuno

AU - Matthiesen, Rune

AU - Pedro, Madalena

AU - Marques, Franklim

AU - Pinto, Madalena M.

AU - Sousa, Emília

AU - Helena Vasconcelos, M.

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PY - 2018/12/12

Y1 - 2018/12/12

N2 - 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.

AB - 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.

KW - Antitumor activity

KW - Cholesterol localization

KW - Non-small cell lung cancer

KW - Rags

KW - Thioxanthones

KW - Tumor xenografts

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