Zhao Jianlei, Wu Shuangshuang, Wang Deying, Edwards Holly, Thibodeau Jenna, Kim Seongho, Stemmer Paul, Wang Guan, Jin Jingji, Savasan Süreyya, Taub Jeffrey W, Ge Yubin
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, PR China; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Department of Pediatric Hematology, The First Hospital of Jilin University, Changchun 130012, PR China.
Biochem Pharmacol. 2024 Oct;228:116065. doi: 10.1016/j.bcp.2024.116065. Epub 2024 Feb 17.
The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.
大多数急性髓系白血病（AML）患者对由阿糖胞苷（AraC）和蒽环类药物组成的强化诱导治疗有反应，尽管超过一半的患者会复发。复发/难治性（R/R）AML患者难以治疗，其临床结局仍然不佳。维奈克拉（VEN）与阿扎胞苷（AZA）联合使用为R/R AML提供了一种有前景的治疗选择，尽管总生存期（OS）仍有待提高（OS为4.3至9.1个月）。c-Myc的过表达与AML的化疗耐药有关。组蛋白去乙酰化酶（HDAC）抑制剂已被证明可抑制c-Myc并增强VEN以及AZA的抗白血病活性，不过这三者联合使用尚未得到充分研究。在本研究中，我们研究了HDAC抑制剂帕比司他与VEN + AZA联合用于抗AraC的AML细胞的作用。帕比司他治疗可下调c-Myc和Bcl-xL并上调Bim，从而增强VEN + AZA对AraC耐药AML细胞的抗白血病活性。此外，单独使用帕比司他以及与VEN + AZA联合使用均可抑制AraC耐药AML细胞中的氧化磷酸化和/或糖酵解。这些发现支持进一步开发帕比司他与VEN + AZA联合用于治疗AraC耐药AML。
