OncoTargets and Therapy (Jul 2019)
The combination of the glycolysis inhibitor 2-DG and sorafenib can be effective against sorafenib-tolerant persister cancer cells
Abstract
Li Wang,1 Qian Yang,2 Shaoyong Peng,3 Xiaoxia Liu1,31Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People’s Republic of China; 2Department of Orthopedics, Luoyang No.1 Hospital of TCM, Luoyang 471000, People’s Republic of China; 3The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, People’s Republic of ChinaBackground: Chemotherapy remains a major clinical option for the successful treatment of cancer by eliminating fast-growing populations of cancer cells. However, drug resistance causes the failure of antitumor treatment. Increasing evidence suggests that a small subpopulation of cancer cells will enter a “persister state” under drug pressure. The persister cell pool constitutes a reservoir from which drug resistance may emerge. Therefore, targeting persister cells presents a therapeutic opportunity to prevent drug resistance and impede tumor relapse.Materials and methods: RT-qPCR, Western blot, Seahorse, apoptosis assay, clonogenic assay, and xenografted mouse model were used for this study.Results: We showed that a similar therapy-resistant cell state underlies the behavior of persister cells derived from sorafenib treatments with reversible, nonmutational mechanisms. Then, we demonstrated that persister cells showed upregulated glycolysis, as evidenced by higher ECAR, as well as increased glucose consumption and lactate production. A database analysis showed that sorafenib-tolerant persister cells exhibited the increased expression of the glycolytic enzyme hexokinase 2, which is closely related to the poor prognosis in liver cancer. We found that the combined treatment with the glycolytic inhibitor 2-DG and sorafenib increased persister cell apoptosis and inhibited colony formation. Consequently, we demonstrated that when persister cells were exposed to a low concentration of sorafenib, they suffered mitochondrial dysfunction but showed compensatory increases in glycolysis, which contributes to cell growth and proliferation. Finally, we showed that the combination of 2-DG and sorafenib reduced persister tumor growth in mice.Conclusions: These findings suggest that such a combination can effectively hamper persister cell growth and may represent a promising therapeutic strategy to prevent persister cell resistance.Keywords: persister cells, drug-resistance, sorafenib, glycolysis inhibitor, antitumor
