- 作者: Szu-Yuan Wu, Yu-Ching Wen, Chia-Chi Ku, Yi-Chieh Yang, Jyh-Ming Chow, Shun-Fa Yang, Wei-Jiunn Lee and Ming-Hsien Chien
- 作者服務機構: 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. Szu-Yuan Wu and Yu-Ching Wen contributed equally to this work. 4. Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 5. Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 6. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 7. Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 8. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 9. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 10.Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 11.Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 12.TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Acute myeloid leukemia, Apoptosis, Autophagy, Protein phosphatase 2 a, Akt, Mitogen-activated protein kinase, Reactive oxygen species, Penfluridol