Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells

Abstract

Hyperglycemia during hyper-CVAD chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL) (Cancer 2004; 100:1179–85). The optimal clinical strategy to manage hyperglycemia during hyper-CVAD is unclear. To examine whether anti-diabetic pharmacotherapy can influence chemosensitivity of ALL cells, we examined the impacts of different anti-diabetic agents on ALL cell lines and patient samples. Pharmacologically achievable concentrations of insulin, aspart and glargine significantly increased the number of ALL cells, and aspart and glargine did so at lower concentrations than human insulin. In contrast, metformin and rosiglitazone significantly decreased the cell number. Human insulin and analogs activated AKT/mTOR signaling and stimulated ALL cell proliferation (as measured by flow cytometric methods), but metformin and rosiglitazone blocked AKT/mTOR signaling and inhibited proliferation. Metformin 500 μM and rosiglitazone 10 μM were found to sensitize Reh cells to daunorubicin, while aspart, glargine and human insulin (all at 1.25 mIU/L) enhanced chemoresistance. Metformin and rosiglitazone enhanced daunorubicin-induced apoptosis, while insulin, aspart and glargine antagonized daunorubicin-induced apoptosis. In addition, metformin increased etoposide-induced and L-asparaginase-induced apoptosis; rosiglitazone increased etoposide-induced and vincristine-induced apoptosis. In conclusion, our results suggest that use of insulins to control hyperglycemia in ALL patients may contribute to anthracycline chemoresistance, while metformin and thiazolidinediones may improve chemosensitivity to anthracycline as well as other chemotherapy drugs through their different impacts on AKT/mTOR signaling in leukemic cells. Our data suggest that the choice of anti-diabetic pharmacotherapy during chemotherapy may influence clinical outcomes in ALL.

Keywords: :

• acute lymphoblastic leukemia
• chemoresistance
• insulin
• metformin
• secretagogues
• thiazolidinediones

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This paper is dedicated to our beloved deceased colleague Dr. Mary Ann Weiser. The University of Texas MD Anderson Cancer Center, Division of Internal Medicine Multidisciplinary Research Program (PI: M. Weiser, succeeded by S.C. Yeung; co-PI: M. Andreeff). This study was also supported by grants from the following agencies: U.S. National Institute of Health (NIHRO1CA 089266, PI: M.H. Lee), Department of Defense, Breast Cancer Research Program (BCRP) of the Office of the Congressionally Directed Medical Research Programs (CDMRP) (Synergistic Idea Development Award BC062166, PI: S.C. Yeung and M.H. Lee), Susan G. Komen Foundation for Breast Cancer Research (Promise grant KG081048, PI: S.C. Yeung), the National Natural Science Fund of China (no. 90713036, PI: J. Pan; no. 30772367, PI: C. Chen), the Research Foundation of Education Bureau of Guangdong Province, China (Grant cxzd1103) to J. Pan, the Research Foundation of Guangzhou Bureau of Science and Technology, China (Grant to J. Pan), National Natural Science Funds of China for Distinguished Young Scholars (grant 81025021, PI: J. Pan), National Basic Research Program of China (973 Program grant 2009CB825506, PI: J. Pan), National High Technology Research and Development Program of China (863 Program grant 2008AA02Z420, PI: J. Pan), the Major Research Plan of the National Natural Science Fund of China (grant 90713036, PI: J. Pan), and the Fundamental Research Funds for Central Universities (PI: J. Pan). Enrique Fuentes-Mattei is supported by the MD Anderson Cancer Center Training Grant Program in Molecular Genetics (T32CA009299, PI: G. Lozano), and Guermarie Velazquez-Torres is supported by a National Cancer Institute grant minority supplement (parent grant R01CA089266, PI: M.H. Lee).

Financial Support

No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The University of Texas MD Anderson Cancer Center, Division of Internal Medicine Multidisciplinary Research Program; This study was also supported by grants from the following agencies: US. National Institute of Health (NIHRO1CA 089266, PI: M.H. Lee), Department of Defense, Breast Cancer Research Program (BCRP) of the Office of the Congressionally Directed Medical Research Programs (CDMRP) (Synergistic Idea Development Award BC062166, PI: S.C. Yeung and M.H. Lee), Susan G. Komen Foundation for Breast Cancer Research (Promise grant KG081048, PI: S.C. Yeung), National Natural Science Funds of China for Distinguished Young Scholars (grant 81025021, PI: J. Pan), National Basic Research Program of China (973 Program grant 2009CB825506, PI: J. Pan), the National Natural Science Fund of China (no. 90713036, PI: J. Pan; no. 30772367, PI: C. Chen), the Research Foundation of Education Bureau of Guangdong Province, China (Grant cxzd1103) to J. Pan, the Research Foundation of Guangzhou Bureau of Science and Technology, China (Grant to J. Pan), National High Technology Research and Development Program of China (863 Program grant 2008AA02Z420, PI: J. Pan), and the Fundamental Research Funds for Central Universities (PI: J. Pan). Enrique Fuentes-Mattei is supported by the MD Anderson Cancer Center Training Grant Program in Molecular Genetics (T32CA009299, PI: G. Lozano) and Guermarie Velazquez-Torres is supported by a National Cancer Institute grant minority supplement (parent grant R01CA089266, PI: M.H. Lee).

Note

Supplemental materials can be found at: 
www.landesbioscience.com/journals/cc/article/20770