Danna Wei1, Tingting Lu1, Dan Ma2, Kunlin Yu1, Tianzhuo Zhang1, Jie Xiong2, Weili Wang1, Zhaoyuan Zhang1, Qin Fang3, Jishi Wang4. 1. Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Department of Guizhou Province Hematopoietic Stem Cell Transplantation Center and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guiyang 550004, PR China; Department of Clinical Medical School, Guizhou Medical University, Guiyang 550004, PR China. 2. Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Department of Guizhou Province Hematopoietic Stem Cell Transplantation Center and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guiyang 550004, PR China. 3. Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550058, PR China. 4. Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Department of Guizhou Province Hematopoietic Stem Cell Transplantation Center and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guiyang 550004, PR China; Department of Clinical Medical School, Guizhou Medical University, Guiyang 550004, PR China. Electronic address: wangjishi9646@163.com.
Abstract
AIMS: The aim of this study was to investigate the combinatorial effects of IM and a novel HDAC inhibitor AR-42 on the proliferation, apoptosis, cell cycle arrest, migration and invasion of CML cells, and to explore the underlying mechanisms. MAIN METHODS: We assessed the ability of the pan-HDAC inhibitor AR-42 and IM, to synergistically kill CML cells by survival, apoptosis, cell cycle, migration and invasion assays in vitro. We also assessed the HDAC1 expression by Western blot and real-time PCR. Synergy was calculated using combinatorial indices as determined by CalcuSyn. KEY FINDINGS: We found that Combining AR-42 with IM synergistically inhibited CML cell proliferation, enhanced cell apoptosis, induced cell cycle arrest, and decreased migration and invasion. The expression of HDAC1 in K562R cells was higher than that in K562 cells. AR-42 enhanced IM-induced HDAC1 expression inhibition in K562 and K562R cells. Importantly, HDAC1 overexpression partly reversed the apoptosis, G2/M phase arrest, migration and invasion of K562 cells induced by the combination of IM with AR-42. Moreover, HDAC1 knockdown partly promoted K562R cell apoptosis and G2/M phase arrest, migration and invasion induced by IM in combination with AR-42. SIGNIFICANCE: In conclusion, AR-42 may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating HDAC1 expression. This study provides new insights into the effects of combined therapy using IM and pan-HDAC inhibitor AR-42, paving the way for overcoming IM resistance in clinical practice.
AIMS: The aim of this study was to investigate the combinatorial effects of IM and a novel HDAC inhibitor AR-42 on the proliferation, apoptosis, cell cycle arrest, migration and invasion of CML cells, and to explore the underlying mechanisms. MAIN METHODS: We assessed the ability of the pan-HDAC inhibitor AR-42 and IM, to synergistically kill CML cells by survival, apoptosis, cell cycle, migration and invasion assays in vitro. We also assessed the HDAC1 expression by Western blot and real-time PCR. Synergy was calculated using combinatorial indices as determined by CalcuSyn. KEY FINDINGS: We found that Combining AR-42 with IM synergistically inhibited CML cell proliferation, enhanced cell apoptosis, induced cell cycle arrest, and decreased migration and invasion. The expression of HDAC1 in K562R cells was higher than that in K562 cells. AR-42 enhanced IM-induced HDAC1 expression inhibition in K562 and K562R cells. Importantly, HDAC1 overexpression partly reversed the apoptosis, G2/M phase arrest, migration and invasion of K562 cells induced by the combination of IM with AR-42. Moreover, HDAC1 knockdown partly promoted K562R cell apoptosis and G2/M phase arrest, migration and invasion induced by IM in combination with AR-42. SIGNIFICANCE: In conclusion, AR-42 may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating HDAC1 expression. This study provides new insights into the effects of combined therapy using IM and pan-HDAC inhibitor AR-42, paving the way for overcoming IM resistance in clinical practice.
Authors: Abdelhakim Bouyahya; Naoufal El Hachlafi; Tarik Aanniz; Ilhame Bourais; Hamza Mechchate; Taoufiq Benali; Mohammad Ali Shariati; Pavel Burkov; José M Lorenzo; Polrat Wilairatana; Mohammad S Mubarak; Nasreddine El Omari Journal: Molecules Date: 2022-04-15 Impact factor: 4.927