Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae

Lis, Paweł; Zarzycki, Marek; Ko, Young Hee; Casal, Margarida; Pedersen, Peter L.; Goffeau, André; Ułaszewski, Stanisław

doi:10.1007/s10863-012-9421-8

Cited by 26 publications

(37 citation statements)

References 37 publications

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“…Moreover, as shown earlier, different levels of Jen1 transporter activity [28] may be responsible for different levels of accumulation of 3-BP and toxicity in the yeast Saccharomyces cerevisiae [29]. 3-BP causes rapid intracellular ATP depletion, that is, before MM cell death.…”

Section: Discussionmentioning

confidence: 95%

Killing multiple myeloma cells with the small molecule 3-bromopyruvate

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 95%

Killing multiple myeloma cells with the small molecule 3-bromopyruvate

et al. 2014

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“…Its effectiveness has been proven in animal experiments, and one case of clinical treatment has been reported [2,[6][7][8]. Importantly, as a polar compound, 3-BP is not a substrate for the PDR network in yeast [9] or the MDR transporters in mammalian cells [10]. A crucial problem in the future clinical application of 3-BP is the prevention of its possible side effects.…”

Section: Introductionmentioning

confidence: 99%

Transport of 3-bromopyruvate across the human erythrocyte membrane

Sadowska-Bartosz¹,

Soszyński

Ułaszewski

et al. 2014

Cellular and Molecular Biology Letters

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3-Bromopyruvic acid (3-BP) is a promising anticancer compound because it is a strong inhibitor of glycolytic enzymes, especially glyceraldehyde 3-phosphate dehydrogenase. The Warburg effect means that malignant cells are much more dependent on glycolysis than normal cells. Potential complications of anticancer therapy with 3-BP are side effects due to its interaction with normal cells, especially erythrocytes. Transport into cells is critical for 3-BP to have intracellular effects. The aim of our study was the kinetic characterization of 3-BP transport into human erythrocytes. 3-BP uptake by erythrocytes was linear within the first 3 min and pH-dependent. The transport rate decreased with increasing pH in the range of 6.0-8.0. The K m and V m values for 3-BP transport were 0.89 mM and 0.94 mmol/(l cells x min), respectively. The transport was inhibited competitively by pyruvate and significantly inhibited by DIDS, SITS, and 1-cyano-4-hydroxycinnamic acid. Flavonoids also inhibited 3-BP transport: the most potent inhibition was found for luteolin and quercetin.

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“…The stringent correlation between 3-BrPA sensitivity and expression of its transporter, but none of the previously identified metabolic targets or transporters 48,50 , suggests that 3-BrPA is likely non-specifically toxic once it enters the cell. Consistent with this, 3-BrPA has non-glycolytic targets, such as V-ATPases 20 , SERCAs 24 , Carbonic Anhydrases 51 and HDACs 52 .…”

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confidence: 97%

“…4). Finally, another monocarboxylate transporter, Jen1p, was recently implicated as the primary carrier of 3-BrPA in yeast 48 . However, this transporter bears no homology to any human gene product.…”

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confidence: 99%

MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors

et al. 2012

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SUMMARYThere is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anti-cancer therapy are underway. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, MCT1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Lastly, forced MCT1 expression in 3-BrPA resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.

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Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae

Cited by 26 publications

References 37 publications

Killing multiple myeloma cells with the small molecule 3-bromopyruvate

Killing multiple myeloma cells with the small molecule 3-bromopyruvate

Transport of 3-bromopyruvate across the human erythrocyte membrane

MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors

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