2. Academic Validation
  3. Penfluridol triggers cytoprotective autophagy and cellular apoptosis through ROS induction and activation of the PP2A-modulated MAPK pathway in acute myeloid leukemia with different FLT3 statuses

Penfluridol triggers cytoprotective autophagy and cellular apoptosis through ROS induction and activation of the PP2A-modulated MAPK pathway in acute myeloid leukemia with different FLT3 statuses

  • J Biomed Sci. 2019 Aug 31;26(1):63. doi: 10.1186/s12929-019-0557-2.
Szu-Yuan Wu 1 2,  Yu-Ching Wen 3 4,  Chia-Chi Ku 5,  Yi-Chieh Yang 5,  Jyh-Ming Chow 6,  Shun-Fa Yang 7 8,  Wei-Jiunn Lee 9 10,  Ming-Hsien Chien 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 4 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6 Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 7 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
  • 8 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
  • 9 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. lwj5905@gmail.com.
  • 10 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. lwj5905@gmail.com.
  • 11 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
  • 12 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
  • 13 Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
  • 14 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
PMID: 31470848 DOI: 10.1186/s12929-019-0557-2
Abstract

Background: Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the cure rates for AML patients remain low, and the notorious adverse effects of chemotherapeutic drugs drastically reduce the life quality of patients. Penfluridol, a long-acting oral antipsychotic drug, has an outstanding safety record and exerts oncostatic effects on various solid tumors. Until now, the effect of penfluridol on AML remains unknown.

Methods: AML cell lines harboring wild-type (WT) Fms-like tyrosine kinase 3 (FLT3) and internal tandem duplication (ITD)-mutated FLT3 were used to evaluate the cytotoxic effects of penfluridol by an MTS assay. A flow cytometric analysis and immunofluorescence staining were employed to determine the cell-death phenotype, cell cycle profile, and Reactive Oxygen Species (ROS) and acidic vesicular organelle (AVO) formation. Western blotting and chemical inhibitors were used to explore the underlying mechanisms involved in penfluridol-mediated cell death.

Results: We observed that penfluridol concentration-dependently suppressed the cell viability of AML cells with FLT3-WT (HL-60 and U937) and FLT3-ITD (MV4-11). We found that penfluridol treatment not only induced Apoptosis as evidenced by increases of nuclear fragmentation, the sub-G1 populations, poly (ADP ribose) polymerase (PARP) cleavage, and Caspase-3 activation, but also triggered autophagic responses, such as the LIGHT chain 3 (LC3) turnover and AVO formation. Interestingly, blocking Autophagy by the pharmacological inhibitors, 3-methyladenine and chloroquine, dramatically enhanced penfluridol-induced Apoptosis, indicating the cytoprotective role of Autophagy in penfluridol-treated AML cells. Mechanistically, penfluridol-induced Apoptosis occurred through activating protein Phosphatase 2A (PP2A) to suppress Akt and mitogen-activated protein kinase (MAPK) activities. Moreover, penfluridol's augmentation of intracellular ROS levels was critical for the penfluridol-induced autophagic response. In the clinic, we observed that patients with AML expressing high PP2A had favorable prognoses.

Conclusions: These findings provide a rationale for penfluridol being used as a PP2A activator for AML treatment, and the combination of penfluridol with an Autophagy Inhibitor may be a novel strategy for AML harboring FLT3-WT and FLT3-ITD.

Keywords

Acute myeloid leukemia; Akt; Apoptosis; Autophagy; Mitogen-activated protein kinase; Penfluridol; Protein phosphatase 2 a; Reactive oxygen species.

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