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Glycolysis inhibition and its effect in doxorubicin resistance in neuroblastoma
Jonathan F Bean1, Yi-Yong Qiu2, Songtao Yu2
1Department of Pediatric Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611; Cancer Biology and Epigenetics, Children's Hospital of Chicago Research Center, Chicago, IL 60641.
Background/Purpose:
A common trait among cancers is the increased level of glycolysis despite adequate oxygen levels to support aerobic respiration. This has been shown repeatedly in different human malignancies. Glycolysis inhibitors, especially 3-bromopyruvate, have been shown to be effective chemotherapeutic agents. The effect of glycolysis inhibition upon chemotherapy resistance is relatively unknown.
Methods:
Wild-type and doxorubicin-resistant lines of neuroblastoma (SK-N-SH and SK-N-Be(2)C) were used in this study. Using an MTT assay, the IC50 of 3-BrPA was determined. Subsequently, doxorubicin-resistant cell lines were treated with 3-bromopyruvate, doxorubicin, and 3-bromopyruvate with doxorubicin. Additionally, a luminescence ATP detection assay was used to measure intracellular ATP levels, and a lactate assay was used to determine intracellular lactate levels. All experiments were repeated in hypoxic conditions.
Results:
Treatment with 3-bromopyruvate and doxorubicin significantly decreased the mean cell viabilities at 24, 48, and 72hours in normoxic conditions. A similar response was replicated in hypoxic conditions. Treatment with 3-bromopyruvate significantly decreased intracellular ATP and lactate levels.
Conclusion:
Glycolysis inhibitors such as 3-bromopyruvate could prove to become an effective means by which chemotherapy resistance can be overcome in human neuroblastoma.
Insights
Glycolysis inhibitors like 3-bromopyruvate can overcome chemotherapy resistance in neuroblastoma. This study shows 3-bromopyruvate reduces cell viability and ATP levels, even in resistant cell lines.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Cancers exhibit increased glycolysis even with sufficient oxygen.
- Glycolysis inhibitors, such as 3-bromopyruvate, show chemotherapeutic potential.
- The impact of glycolysis inhibition on chemotherapy resistance remains largely unexplored.
Purpose of the Study:
- To investigate the effect of glycolysis inhibition on chemotherapy resistance in neuroblastoma.
- To evaluate 3-bromopyruvate as a potential agent to overcome doxorubicin resistance.
Main Methods:
- Utilized wild-type and doxorubicin-resistant neuroblastoma cell lines (SK-N-SH, SK-N-Be(2)C).
- Determined IC50 of 3-bromopyruvate (3-BrPA) using MTT assay.
- Assessed effects of 3-BrPA, doxorubicin, and combination therapy on cell viability, intracellular ATP, and lactate levels under normoxic and hypoxic conditions.
Main Results:
- Combined treatment with 3-bromopyruvate and doxorubicin significantly reduced neuroblastoma cell viability in both normoxic and hypoxic conditions.
- 3-bromopyruvate treatment led to significant reductions in intracellular ATP and lactate levels.
- Similar efficacy was observed across different time points (24, 48, 72 hours).
Conclusions:
- Glycolysis inhibition using 3-bromopyruvate demonstrates potential in overcoming chemotherapy resistance in human neuroblastoma.
- 3-bromopyruvate may serve as a valuable therapeutic strategy to enhance conventional chemotherapy efficacy.
- Further research is warranted to explore clinical applications.
