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Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer

SIMPLE SUMMARY: Drug repurposing has been effective for discovering novel treatments for cancer. The antipsychotic agent penfluridol was reported to suppress lung cancer growth via ATP energy deprivation. The aim of our study was to investigate how penfluridol influences energy metabolism in lung ca...

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Autores principales: Lai, Tsung-Ching, Lee, Yueh-Lun, Lee, Wei-Jiunn, Hung, Wen-Yueh, Cheng, Guo-Zhou, Chen, Ji-Qing, Hsiao, Michael, Chien, Ming-Hsien, Chang, Jer-Hwa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179427/
https://www.ncbi.nlm.nih.gov/pubmed/35681729
http://dx.doi.org/10.3390/cancers14112750
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author Lai, Tsung-Ching
Lee, Yueh-Lun
Lee, Wei-Jiunn
Hung, Wen-Yueh
Cheng, Guo-Zhou
Chen, Ji-Qing
Hsiao, Michael
Chien, Ming-Hsien
Chang, Jer-Hwa
author_facet Lai, Tsung-Ching
Lee, Yueh-Lun
Lee, Wei-Jiunn
Hung, Wen-Yueh
Cheng, Guo-Zhou
Chen, Ji-Qing
Hsiao, Michael
Chien, Ming-Hsien
Chang, Jer-Hwa
author_sort Lai, Tsung-Ching
collection PubMed
description SIMPLE SUMMARY: Drug repurposing has been effective for discovering novel treatments for cancer. The antipsychotic agent penfluridol was reported to suppress lung cancer growth via ATP energy deprivation. The aim of our study was to investigate how penfluridol influences energy metabolism in lung cancer cells. We observed that penfluridol inhibited mitochondrial oxidative phosphorylation (OXPHOS), but induced glycolysis to compensate for the loss of ATP caused by suppression of mitochondrial OXPHOS. We also confirmed that inhibition of glycolysis by 2-deoxy-D-glucose (2DG) significantly augmented the antitumor effects caused by penfluridol in vitro and in vivo. Our studies provide novel insights into repurposing penfluridol combined with 2-DG for lung cancer treatment. ABSTRACT: Energy metabolism is the basis for cell growth, and cancer cells in particular, are more energy-dependent cells because of rapid cell proliferation. Previously, we found that penfluridol, an antipsychotic drug, has the ability to trigger cell growth inhibition of lung cancer cells via inducing ATP energy deprivation. The toxic effect of penfluridol is related to energy metabolism, but the underlying mechanisms remain unclear. Herein, we discovered that treatment of A549 and HCC827 lung cancer cells with penfluridol caused a decrease in the total amount of ATP, especially in A549 cells. An Agilent Seahorse ATP real-time rate assay revealed that ATP production rates from mitochondrial respiration and glycolysis were, respectively, decreased and increased after penfluridol treatment. Moreover, the amount and membrane integrity of mitochondria decreased, but glycolysis-related proteins increased after penfluridol treatment. Furthermore, we observed that suppression of glycolysis by reducing glucose supplementation or using 2-deoxy-D-glucose (2DG) synergistically enhanced the inhibitory effect of penfluridol on cancer cell growth and the total amount of mitochondria. A mechanistic study showed that the penfluridol-mediated energy reduction was due to inhibition of critical regulators of mitochondrial biogenesis, the sirtuin 1 (SIRT1)/peroxisome-proliferator-activated receptor co-activator-1α (PGC-1α) axis. Upregulation of the SIRT1/PGC-1α axis reversed the inhibitory effect of penfluridol on mitochondrial biogenesis and cell viability. Clinical lung cancer samples revealed a positive correlation between PGC-1α (PPARGC1A) and SIRT1 expression. In an orthotopic lung cancer mouse model, the anticancer activities of penfluridol, including growth and metastasis inhibition, were also enhanced by combined treatment with 2DG. Our study results strongly support that a combination of repurposing penfluridol and a glycolysis inhibitor would be a good strategy for enhancing the anticancer activities of penfluridol in lung cancer.
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spelling pubmed-91794272022-06-10 Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer Lai, Tsung-Ching Lee, Yueh-Lun Lee, Wei-Jiunn Hung, Wen-Yueh Cheng, Guo-Zhou Chen, Ji-Qing Hsiao, Michael Chien, Ming-Hsien Chang, Jer-Hwa Cancers (Basel) Article SIMPLE SUMMARY: Drug repurposing has been effective for discovering novel treatments for cancer. The antipsychotic agent penfluridol was reported to suppress lung cancer growth via ATP energy deprivation. The aim of our study was to investigate how penfluridol influences energy metabolism in lung cancer cells. We observed that penfluridol inhibited mitochondrial oxidative phosphorylation (OXPHOS), but induced glycolysis to compensate for the loss of ATP caused by suppression of mitochondrial OXPHOS. We also confirmed that inhibition of glycolysis by 2-deoxy-D-glucose (2DG) significantly augmented the antitumor effects caused by penfluridol in vitro and in vivo. Our studies provide novel insights into repurposing penfluridol combined with 2-DG for lung cancer treatment. ABSTRACT: Energy metabolism is the basis for cell growth, and cancer cells in particular, are more energy-dependent cells because of rapid cell proliferation. Previously, we found that penfluridol, an antipsychotic drug, has the ability to trigger cell growth inhibition of lung cancer cells via inducing ATP energy deprivation. The toxic effect of penfluridol is related to energy metabolism, but the underlying mechanisms remain unclear. Herein, we discovered that treatment of A549 and HCC827 lung cancer cells with penfluridol caused a decrease in the total amount of ATP, especially in A549 cells. An Agilent Seahorse ATP real-time rate assay revealed that ATP production rates from mitochondrial respiration and glycolysis were, respectively, decreased and increased after penfluridol treatment. Moreover, the amount and membrane integrity of mitochondria decreased, but glycolysis-related proteins increased after penfluridol treatment. Furthermore, we observed that suppression of glycolysis by reducing glucose supplementation or using 2-deoxy-D-glucose (2DG) synergistically enhanced the inhibitory effect of penfluridol on cancer cell growth and the total amount of mitochondria. A mechanistic study showed that the penfluridol-mediated energy reduction was due to inhibition of critical regulators of mitochondrial biogenesis, the sirtuin 1 (SIRT1)/peroxisome-proliferator-activated receptor co-activator-1α (PGC-1α) axis. Upregulation of the SIRT1/PGC-1α axis reversed the inhibitory effect of penfluridol on mitochondrial biogenesis and cell viability. Clinical lung cancer samples revealed a positive correlation between PGC-1α (PPARGC1A) and SIRT1 expression. In an orthotopic lung cancer mouse model, the anticancer activities of penfluridol, including growth and metastasis inhibition, were also enhanced by combined treatment with 2DG. Our study results strongly support that a combination of repurposing penfluridol and a glycolysis inhibitor would be a good strategy for enhancing the anticancer activities of penfluridol in lung cancer. MDPI 2022-06-01 /pmc/articles/PMC9179427/ /pubmed/35681729 http://dx.doi.org/10.3390/cancers14112750 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lai, Tsung-Ching
Lee, Yueh-Lun
Lee, Wei-Jiunn
Hung, Wen-Yueh
Cheng, Guo-Zhou
Chen, Ji-Qing
Hsiao, Michael
Chien, Ming-Hsien
Chang, Jer-Hwa
Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer
title Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer
title_full Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer
title_fullStr Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer
title_full_unstemmed Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer
title_short Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer
title_sort synergistic tumor inhibition via energy elimination by repurposing penfluridol and 2-deoxy-d-glucose in lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179427/
https://www.ncbi.nlm.nih.gov/pubmed/35681729
http://dx.doi.org/10.3390/cancers14112750
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