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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.
Afiliación
  • Lai TC; Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
  • Lee YL; Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
  • Lee WJ; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • Hung WY; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • Cheng GZ; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
  • Chen JQ; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • Hsiao M; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • Chien MH; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • Chang JH; Department of Cancer Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA.
Cancers (Basel) ; 14(11)2022 Jun 01.
Article en En | MEDLINE | ID: mdl-35681729
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2022 Tipo del documento: Article País de afiliación: Taiwán

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2022 Tipo del documento: Article País de afiliación: Taiwán