AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

Autor: Jia J; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.; University of Science and Technology of China, Hefei, 230026, China.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China., Ji W; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.; University of Science and Technology of China, Hefei, 230026, China.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China., Saliba AN; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Csizmar CM; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA., Ye K; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China., Hu L; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.; University of Science and Technology of China, Hefei, 230026, China.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China., Peterson KL; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Schneider PA; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Meng XW; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Venkatachalam A; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Patnaik MM; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Webster JA; Adult Leukemia Program, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, 21287, USA., Smith BD; Adult Leukemia Program, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, 21287, USA., Ghiaur G; Adult Leukemia Program, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, 21287, USA., Wu X; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Zhong J; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Pandey A; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.; Manipal Academy of Higher Education, Manipal, 576104, Kamataka, India., Flatten KS; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA., Deng Q; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China., Wang H; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China., Kaufmann SH; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA. Kaufmann.Scott@Mayo.edu.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA. Kaufmann.Scott@Mayo.edu.; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. Kaufmann.Scott@Mayo.edu., Dai H; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. daih@cmpt.ac.cn.; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. daih@cmpt.ac.cn.; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. daih@cmpt.ac.cn.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Apr; Vol. 31 (4), pp. 405-416. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1038/s41418-024-01283-9
Abstrakt: BH3 mimetics, including the BCL2/BCLX L /BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLX L inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLX L . Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.
(© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Databáze: MEDLINE
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