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Killing multiple myeloma cells with the small molecule 3-bromopyruvate: implications for therapy
Grażyna Majkowska-Skrobek1, Daria Augustyniak, Paweł Lis
1aInstitute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland bInstitute of Cell Biology, NAS of Ukraine, Lviv, Ukraine cKoDiscovery LLC, UM BioPark, Innovation Center dDepartments of Biological Chemistry and Oncology, Member Sidney Kimmel Comprehensive Cancer Center, Member Center for Obesity Research and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA eInstitute of Life Sciences, Catholic University of Louvain, Place de l'Université, Louvain-la-Neuve, Belgium.
Abstract:
The small molecule 3-bromopyruvate (3-BP), which has emerged recently as the first member of a new class of potent anticancer agents, was tested for its capacity to kill multiple myeloma (MM) cancer cells. Human MM cells (RPMI 8226) begin to lose viability significantly within 8 h of incubation in the presence of 3-BP. The Km (0.3 mmol/l) for intracellular accumulation of 3-BP in MM cells is 24 times lower than that in control cells (7.2 mmol/l). Therefore, the uptake of 3-BP by MM cells is significantly higher than that by peripheral blood mononuclear cells. Further, the IC50 values for human MM cells and control peripheral blood mononuclear cells are 24 and 58 µmol/l, respectively. Therefore, specificity and selectivity of 3-BP toward MM cancer cells are evident on the basis of the above. In MM cells the transcription levels of the gene encoding the monocarboxylate transporter MCT1 is significantly amplified compared with control cells. The level of intracellular ATP in MM cells decreases by over 90% within 1 h after addition of 100 µmol/l 3-BP. The cytotoxicity of 3-BP, exemplified by a marked decrease in viability of MM cells, is potentiated by the inhibitor of glutathione synthesis buthionine sulfoximine. In addition, the lack of mutagenicity and its superior capacity relative to Glivec to kill MM cancer cells are presented in this study.
Insights
The small molecule 3-bromopyruvate (3-BP) effectively kills multiple myeloma cancer cells by targeting their unique metabolic pathways. This potent anticancer agent demonstrates significant selectivity for cancer cells over healthy cells.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Multiple myeloma (MM) is a cancer of plasma cells.
- 3-bromopyruvate (3-BP) is a novel small molecule with anticancer properties.
Purpose of the Study:
- To investigate the efficacy and selectivity of 3-bromopyruvate (3-BP) against multiple myeloma (MM) cancer cells.
- To elucidate the mechanisms underlying 3-BP's action in MM cells.
Main Methods:
- In vitro incubation of human MM cells (RPMI 8226) and peripheral blood mononuclear cells with 3-BP.
- Measurement of intracellular 3-BP accumulation, IC50 values, gene transcription levels (MCT1), and intracellular ATP levels.
- Assessment of 3-BP's cytotoxicity and mutagenicity.
Main Results:
- 3-BP significantly reduced MM cell viability within 8 hours.
- MM cells exhibited a 24-fold lower Km for 3-BP uptake compared to control cells, indicating higher accumulation.
- The IC50 for MM cells (24 µmol/l) was significantly lower than for control cells (58 µmol/l), demonstrating selectivity.
- MCT1 gene transcription was amplified in MM cells, and intracellular ATP levels dropped by over 90% within 1 hour.
- 3-BP showed no mutagenicity and outperformed Glivec in killing MM cells.
Conclusions:
- 3-bromopyruvate exhibits potent and selective cytotoxicity against multiple myeloma cancer cells.
- Enhanced uptake via MCT1 and rapid ATP depletion are key mechanisms of 3-BP's action in MM cells.
- 3-BP represents a promising therapeutic agent for multiple myeloma with a favorable safety profile.
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