Targeting the autophagy in bone marrow stromal cells overcomes resistance to vorinostat in chronic lymphocytic leukemia
Received 7 April 2018
Accepted for publication 23 June 2018
Published 24 August 2018 Volume 2018:11 Pages 5151—5170
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Samir Farghaly
Lu Ding,1,2,* Wan Zhang,1,* Lili Yang,3,* Helene Pelicano,4 Kaiwen Zhou,5 Ran Yin,1 Ruibin Huang,1 Junyi Zeng1
1Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, China; 2School of Basic Medical Sciences, Nanchang University, Nanchang, China; 3Department of Hematology, People’s Hospital of Jiangxi Province, Nanchang, China; 4Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5The First Clinical Medical College, School of Medicine, Nanchang University, Nanchang, China
*These authors contributed equally to this work
Background: The bone marrow microenvironment constitutes a sanctuary for leukemia cells. Recent evidence indicates that environment-mediated drug resistance arises from a reciprocal influence between tumor cells and the surrounding stroma. The present study aimed to investigate the effect of chronic lymphocytic leukemia (CLL) cells on the metabolism of bone marrow stroma, to determine the role of this metabolic change in the stroma in vorinostat resistance of CLL cells, and thus to assess a novel strategy to target stroma and achieve the maximum therapeutic effect of vorinostat.
Methods: To evaluate this issue, we used freshly isolated CLL cells from peripheral blood samples of patients with CLL, and co-cultured them with bone marrow stromal cell lines to examine autophagy activity and metabolic changes in both CLL cells and stromal cells after vorinostat treatment.
Results: The results demonstrated that CLL cells were under intrinsic oxidative stress which was further enhanced by vorinostat treatment, and released H2O2 outside the cells. The adjacent stromal cells took up H2O2 and drove autophagy, mitophagy and glycolysis, resulting in the local production of high-energy mitochondrial fuels, which were then taken up by CLL cells to be effectively utilized through mitochondrial oxidative phosphorylation to enable more ATP production. Notably, targeting autophagic stromal cells with autophagy inhibitor remarkably decreased stromal protection against vorinostat treatment in CLL cells.
Conclusion: This study demonstrated that the stroma in the CLL microenvironment is abnormal and undergoes autophagy, and manipulation of autophagic stromal cells could serve as a novel promising strategy to circumvent stroma-mediated drug resistance in CLL cells.
Keywords: autophagy, chronic lymphocytic leukemia, bone marrow stroma, drug resistance, reactive oxygen species, vorinostat
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