Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin

Abstract

Chronic lymphocytic leukemia (CLL) remains fatal due to the development of resistance to existing therapies. Targeting abnormal glucose metabolism sensitizes various cancer cells to chemotherapy and/or elicits toxicity. Examination of glucose dependency in CLL demonstrated variable sensitivity to glucose deprivation. Further evaluation of metabolic dependencies of CLL cells resistant to glucose deprivation revealed increased engagement of fatty acid oxidation upon glucose withdrawal. Investigation of glucose transporter expression in CLL reveals up-regulation of glucose transporter GLUT4. Treatment of CLL cells with human immunodeficiency (HIV) protease inhibitor ritonavir, which inhibits GLUT4, elicits toxicity similar to that elicited upon glucose deprivation. CLL cells resistant to ritonavir are sensitized by co-treatment with metformin, potentially targeting compensatory mitochondrial complex 1 activity. Ritonavir and metformin have been administered in humans for the treatment of diabetes in patients with HIV, demonstrating the tolerance to this combination in humans. Our studies strongly substantiate further investigation of Food and Drug Administration approved ritonavir and metformin for CLL.

Keywords::

• Basic biology
• chemotherapeutic approaches
• lymphoid leukemia
• signal transduction

Acknowledgements

The authors thank Vivian Liu for her assistance with purification of CLL cells from patient samples. We thank Dr. Elena A. Monclus and the Chandel Laboratory at Northwestern University for assistance with the Seahorse analyzer and helpful discussions.

This work was made possible by the Northwestern University Cell Imaging Facility and a Cancer Center Support Grant (NCI CA060553), the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553), National Institutes of Health/National Cancer Institute grant T32CA079447-13 to K. U. Adekola, American Cancer Society Illinois Division, grant 188679 to M. Shanmugam, American Cancer Society Research Scholar grant RSG-11-254-01-CSM to M. Shanmugam and a R.H.L.C. Cancer Center Gift fund to S. Rosen.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

Supplementary material available online

Supplementary Tables I and II showing further results