Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment

Abstract To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural modification of the arylbiguanide scaffold. We then conducted biological screening using hypoxia inducible factor (HIF)-1-...

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Autores principales:	Takayuki Sakai, Yoshiyuki Matsuo, Kensuke Okuda, Kiichi Hirota, Mieko Tsuji, Tasuku Hirayama, Hideko Nagasawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6759b22745514a5c8c9a25f41acea83c
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spelling	oai:doaj.org-article:6759b22745514a5c8c9a25f41acea83c2021-12-02T15:54:14ZDevelopment of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment10.1038/s41598-021-83708-w2045-2322https://doaj.org/article/6759b22745514a5c8c9a25f41acea83c2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83708-whttps://doaj.org/toc/2045-2322Abstract To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural modification of the arylbiguanide scaffold. We then conducted biological screening using hypoxia inducible factor (HIF)-1- and unfolded protein response (UPR)-dependent reporter assays and selective cytotoxicity assay under low glucose conditions. Homologation studies of aryl-(CH2)n-biguanides (n = 0–6) yielded highly potent derivatives with an appropriate alkylene linker length (n = 5, 6). The o-chlorophenyl derivative 7l (n = 5) indicated the most potent inhibitory effects on HIF-1- and UPR-mediated transcriptional activation (IC50; 1.0 ± 0.1 μM, 7.5 ± 0.1 μM, respectively) and exhibited selective cytotoxicity toward HT29 cells under low glucose condition (IC50; 1.9 ± 0.1 μM). Additionally, the protein expression of HIF-1α induced by hypoxia and of GRP78 and GRP94 induced by glucose starvation was markedly suppressed by the biguanides, thereby inhibiting angiogenesis. Metabolic flux and fluorescence-activated cell sorting analyses of tumor cells revealed that the biguanides strongly inhibited oxidative phosphorylation and activated compensative glycolysis in the presence of glucose, whereas both were strongly suppressed in the absence of glucose, resulting in cellular energy depletion and apoptosis. These findings suggest that the pleiotropic effects of these biguanides may contribute to more selective and effective killing of cancer cells due to the suppression of various stress adaptation systems in the tumor microenvironment.Takayuki SakaiYoshiyuki MatsuoKensuke OkudaKiichi HirotaMieko TsujiTasuku HirayamaHideko NagasawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takayuki Sakai Yoshiyuki Matsuo Kensuke Okuda Kiichi Hirota Mieko Tsuji Tasuku Hirayama Hideko Nagasawa Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
description	Abstract To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural modification of the arylbiguanide scaffold. We then conducted biological screening using hypoxia inducible factor (HIF)-1- and unfolded protein response (UPR)-dependent reporter assays and selective cytotoxicity assay under low glucose conditions. Homologation studies of aryl-(CH2)n-biguanides (n = 0–6) yielded highly potent derivatives with an appropriate alkylene linker length (n = 5, 6). The o-chlorophenyl derivative 7l (n = 5) indicated the most potent inhibitory effects on HIF-1- and UPR-mediated transcriptional activation (IC50; 1.0 ± 0.1 μM, 7.5 ± 0.1 μM, respectively) and exhibited selective cytotoxicity toward HT29 cells under low glucose condition (IC50; 1.9 ± 0.1 μM). Additionally, the protein expression of HIF-1α induced by hypoxia and of GRP78 and GRP94 induced by glucose starvation was markedly suppressed by the biguanides, thereby inhibiting angiogenesis. Metabolic flux and fluorescence-activated cell sorting analyses of tumor cells revealed that the biguanides strongly inhibited oxidative phosphorylation and activated compensative glycolysis in the presence of glucose, whereas both were strongly suppressed in the absence of glucose, resulting in cellular energy depletion and apoptosis. These findings suggest that the pleiotropic effects of these biguanides may contribute to more selective and effective killing of cancer cells due to the suppression of various stress adaptation systems in the tumor microenvironment.
format	article
author	Takayuki Sakai Yoshiyuki Matsuo Kensuke Okuda Kiichi Hirota Mieko Tsuji Tasuku Hirayama Hideko Nagasawa
author_facet	Takayuki Sakai Yoshiyuki Matsuo Kensuke Okuda Kiichi Hirota Mieko Tsuji Tasuku Hirayama Hideko Nagasawa
author_sort	Takayuki Sakai
title	Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
title_short	Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
title_full	Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
title_fullStr	Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
title_full_unstemmed	Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
title_sort	development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6759b22745514a5c8c9a25f41acea83c
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Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment

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