Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis

Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cance...

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Autores principales:	Aya Al-Azawi, Shahrazad Sulaiman, Kholoud Arafat, Javed Yasin, Abderrahim Nemmar, Samir Attoub
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	lung cancer dichloroacetate pyruvate dehydrogenase kinase inhibitor tumor growth angiogenesis gefitinib Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/c5c9c3cf955e4727b2ab0e54c79be468
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spelling	oai:doaj.org-article:c5c9c3cf955e4727b2ab0e54c79be4682021-11-25T17:57:45ZImpact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis10.3390/ijms2222125531422-00671661-6596https://doaj.org/article/c5c9c3cf955e4727b2ab0e54c79be4682021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12553https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.Aya Al-AzawiShahrazad SulaimanKholoud ArafatJaved YasinAbderrahim NemmarSamir AttoubMDPI AGarticlelung cancerdichloroacetatepyruvate dehydrogenase kinase inhibitortumor growthangiogenesisgefitinibBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12553, p 12553 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	lung cancer dichloroacetate pyruvate dehydrogenase kinase inhibitor tumor growth angiogenesis gefitinib Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	lung cancer dichloroacetate pyruvate dehydrogenase kinase inhibitor tumor growth angiogenesis gefitinib Biology (General) QH301-705.5 Chemistry QD1-999 Aya Al-Azawi Shahrazad Sulaiman Kholoud Arafat Javed Yasin Abderrahim Nemmar Samir Attoub Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis
description	Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.
format	article
author	Aya Al-Azawi Shahrazad Sulaiman Kholoud Arafat Javed Yasin Abderrahim Nemmar Samir Attoub
author_facet	Aya Al-Azawi Shahrazad Sulaiman Kholoud Arafat Javed Yasin Abderrahim Nemmar Samir Attoub
author_sort	Aya Al-Azawi
title	Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis
title_short	Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis
title_full	Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis
title_fullStr	Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis
title_full_unstemmed	Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis
title_sort	impact of sodium dichloroacetate alone and in combination therapies on lung tumor growth and metastasis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c5c9c3cf955e4727b2ab0e54c79be468
work_keys_str_mv	AT ayaalazawi impactofsodiumdichloroacetatealoneandincombinationtherapiesonlungtumorgrowthandmetastasis AT shahrazadsulaiman impactofsodiumdichloroacetatealoneandincombinationtherapiesonlungtumorgrowthandmetastasis AT kholoudarafat impactofsodiumdichloroacetatealoneandincombinationtherapiesonlungtumorgrowthandmetastasis AT javedyasin impactofsodiumdichloroacetatealoneandincombinationtherapiesonlungtumorgrowthandmetastasis AT abderrahimnemmar impactofsodiumdichloroacetatealoneandincombinationtherapiesonlungtumorgrowthandmetastasis AT samirattoub impactofsodiumdichloroacetatealoneandincombinationtherapiesonlungtumorgrowthandmetastasis
_version_	1718411828091944960

Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis

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