J Cancer 2017; 8(13):2636-2642. doi:10.7150/jca.19873 This issue

Short Research Communication

Metformin Sensitizes Leukemia Cells to Vincristine via Activation of AMP-activated Protein Kinase

Yong Yi1#, Linfeng Gao1#, Min Wu1,3#, Juan Ao1, Chunyan Zhang1, Xiaodong Wang2, Min Lin2, Johann Bergholz4, Yujun Zhang1, Zhi-Xiong Jim Xiao1✉

1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064. China
2. Hematology Department, Outpatient Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China
3. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
4. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
# These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Yi Y, Gao L, Wu M, Ao J, Zhang C, Wang X, Lin M, Bergholz J, Zhang Y, Xiao ZXJ. Metformin Sensitizes Leukemia Cells to Vincristine via Activation of AMP-activated Protein Kinase. J Cancer 2017; 8(13):2636-2642. doi:10.7150/jca.19873. Available from https://www.jcancer.org/v08p2636.htm

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Vincristine is extensively used chemotherapeutic medicine to treat leukemia. However, it remains a critical clinical problem with regard to its toxicity and drug-resistance. AMP-activated protein kinase (AMPK) is an energy sensor that is pivotal in maintaining cell metabolic homeostasis. It is reported that AMPK is involved in vincristine-induced apoptosis. However, whether AMPK is involved in chemotherapy-resistance is largely unclear. It is well-documented that metformin, a widely used medicine to treat type II diabetes, possesses anti-cancer activities, yet whether metformin affects leukemia cell viability via vincristine is unknown. In this study, we showed that both AMPKα1 mRNA and phosphorylated AMPK protein levels were significantly decreased in clinical leukemia samples. We further demonstrated that metformin sensitized leukemia cells to vincristine-induced apoptosis in an AMPK-dependent manner. In addition, knockdown of AMPKα1 significantly reduced the effects of metformin on vincristine-induced apoptosis. Taken together, these results indicate that AMPK activation is critical in metformin effects on vincristine-induced apoptosis and suggest a putative strategy of a combination therapy using metformin and vincristine in treatment of leukemia.

Keywords: Leukemia, Vincristine, Metformin, AMP-activated Protein Kinase, Apoptosis, Combination Therapy