Abstract 3531: Glycolysis inhibition and its effect in doxorubicin resistance in neuroblastoma
Authors: Fei Chu, Yiyong Qiu, Sandra Clark, Kathryn Solka, Mary Beth Madonna
Journal: Cancer Research (2018)

Abstract Most cancer cells exhibit increased glycolysis and use this metabolic pathway to generate ATP (Adenosine triphosphate) as the main source of their energy supply. This phenomenon is known as the Warburg effect and is considered a fundamental metabolic alteration during malignant transformation. Increased glycolysis results in elevated production of lactate, which leads to acidification of tumor tissue and provides a microenvironment that promotes and selects cellular resistance to drugs. Thus, inhibition of glycolysis may lead to more effective treatment strategies for dealing with drug resistance. 3-Bromopyruvate (3-BrPA), an inhibitor of hexokinase II and an inhibitor of glycolysis, has been shown to be a potent chemotherapeutic agent. Despite many studies showing the efficacy of 3-BrPA against various cancer cells, there have been relatively few studies examining the effects of 3-BrPA on the anti-cancer effects of doxorubicin (Dox) in doxorubicin-resistant (DoxR) human neuroblastoma. The purpose of this study is to examine the effects of 3-BrPA upon DoxR human neuroblastoma cells to treatment with doxorubicin. In present study, we have found that 3-BrPA enhances the response of DoxR neuroblastoma to treatment with Dox and this enhancement exists in both normoxic conditions as well as hypoxic conditions. The results also suggested that this increased response of DoxR cells to treatment with Dox is mediated through decreased intracellular levels of ATP. Additionally the lactate assay revealed that intracellular lactate levels were decreased in neuroblastoma lines when glycolysis was inhibited with 3-BrPA. In order to determine if 3-BrPA, either alone or in combination with cytotoxic drugs, will lead to maximal efficacy of treating of drug-resistant tumor xenografts in vivo. Animal experiments were carried out to study the effects of 3-BrPA in drug-resistant neuroblastoma in nude mice. We have found that 3-BrPA combined with doxorubicin provided significant reduction in tumor size and the rate of tumor growth in mice. The efficacy of doxorubicin itself (88% reduction in tumor volume) overshadowed any effect of cotreatment with 3-BrPA on the Wild type tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy as expected, but co-treatment with 3-BrPA suppressed tumor growth with an 80% reduction in tumor volume. These studies pave the way to determine whether inhibition of glycolysis may be an effective strategy to kill neuroblastoma cells and overcome drug resistance associated with hypoxic conditions. This novel approach may have broad applications in cancer treatment, considering the prevalent Warburg effect observed in a wide array of human cancers. Citation Format: Fei Chu, Yiyong Qiu, Sandra Clark, Kathryn Solka, Mary Beth Madonna. Glycolysis inhibition and its effect in doxorubicin resistance in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3531.