Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death

Yadav, Saveg; Kujur, Praveen Kumar; Pandey, Shrish Kumar; Goel, Yugal; Maurya, Babu Nandan; Verma, Ashish; Kumar, Ajay; Singh, Rana P.; Singh, Sukh Mahendra

doi:10.1016/j.taap.2017.12.004

Cited by 14 publications

(21 citation statements)

References 55 publications

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“…Previous studies revealed that cytochrome c release was involved in 3-BrPA-induced cell apoptosis [42], but no release of cytochrome c was found in the above study [58]. However, the following studies further showed 3-BrPA treatment resulted in an increase of cytochrome c release [59,60], along with an elevated expression of active proapoptotic caspase-3 and a decrease of antiapoptotic Bcl-2 and Mcl-1 [59]. Several recent studies indicated that 3-BrPA also inhibited the expression of HK-II at mRNA and protein levels [59,61].…”

Section: Properties Mechanism Of Action and Cellular Targets Of mentioning

confidence: 81%

“…For example, in HL60 human myeloid leukemia cells, 3-BrPA induced both apoptosis and necrosis at 20–30 μM and an almost exclusively necrotic response at 60 μM [86]. The special manner of cell death induced by 3-BrPA has been supported by multiple in vitro and in vivo studies [19,41,53,60,77,88,89].…”

Section: Antitumor Effects Of 3-brpa and The Underlying Mechanismmentioning

confidence: 99%

“…It should be noted that two recent studies comprehensively described the effects of 3-BrPA on the homeostasis and tumor microenvironment (TME) of tumor-bearing animals, which would assist in optimizing therapeutic regimen of 3-BrPA in future clinical oncology [60,122]. In the first study, 3-BrPA exhibited protective and recuperative effects on the immunological, splenic, hepatic, and renal homeostasis in DL tumor-bearing mice, including reversion of tumor growth associated thymic atrophy and organomegaly (splenomegaly, hepatomegaly, and renomegaly), activation of tumor associated macrophages mediated by IFN-γ, increase of blood leukocytes (CD4+, CD8+ T lymphocytes, and NK cells) and IL-2 receptor expressing cells, alteration of serum cytokine balance, reduction of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) [122].…”

Section: Antitumor Effects Of 3-brpa and The Underlying Mechanismmentioning

confidence: 99%

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Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

Fan

Sun

et al. 2019

Cancers

127

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Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.

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Section: Properties Mechanism Of Action and Cellular Targets Of mentioning

confidence: 81%

Section: Antitumor Effects Of 3-brpa and The Underlying Mechanismmentioning

confidence: 99%

Section: Antitumor Effects Of 3-brpa and The Underlying Mechanismmentioning

confidence: 99%

See 1 more Smart Citation

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

Fan

Sun

et al. 2019

Cancers

127

View full text Add to dashboard Cite

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“…In this study, 3-BPA at low concentrations (0.48µM-62.5µM) appears to work by increasing the ROS levels, 88,89 but 3-BPA at higher concentrations (62.5µM-1000µM) appears to work by decreasing the ROS levels. 90 On the other hand, higher concentrations of SC-514 (125µM) appear to upregulate ROS levels. This conflicting effect between 3-BPA and SC-514 explains why the combination treatment (SC-514 + 3-BPA) gave a lower ROS level compared to the single treatment with either 3-BPA or SC-514.…”

Section: Nbt Assay Measuring the Ros Levelmentioning

confidence: 99%

Interaction between 3-Bromopyruvate and SC-514 in prostate cancer treatment

Famuyiwa¹,

Jebelli²,

Diaka³

et al. 2018

JCPCR

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Background: Prostate cancer (PCA) is the second most diagnosed cancer in men. The high incidence of prostate cancer has been attributed to failures in single treatment of chemotherapy. Failure of mono treatment is mediated by heterogeneity and plasticity of prostate cancer cells. 3-Bromopyruvate is one of the most common chemotherapeutic drugs used for the treatment of prostate cancer. However, its clinical therapeutic efficiency has been limited due to numerous side effects and drug resistance. SC-514 is a relatively new drug. Very little information exists on the anti-cancer effects of SC-514. Nevertheless, SC-514 might be able to overcome side effects of conventional chemotherapy. 3-BPA is strong potentiators of chemotherapeutic drug. 3-BPA has the potential to potentiate the anti-cancer activity of SC-514. The combination of 3-BPA and SC-514 might be able to inhibit prostate cancer carcinogenesis despite existence of heterogeneity and plasticity of prostate cancer cells. Objective of study: This study aims to investigate the potential interaction between 3-BPA and SC-514 during treatment of prostate cancer. Method: The bioassays used in this study include: trypan blue exclusion, MTT tetrazolium, NBT, LDH cytotoxicity, and poly caspase assay. Combination Index (CI) calculation was used to investigate the antagonistic, synergistic or additive interaction between 3-BPA and SC-514. One-way ANOVA was utilized to compare the cytotoxic effects of 3-BPA, SC-514 and the combination of 3-BPA and SC-514 on DU-145 cells and PC-3 cells prostate cancer cells. Results: Results suggested a weak negative (r=-0.29) to moderate negative (r=-0.42) correlation between ROS released and cell death. In addition, there was a weak correlation (r=0.19) between percentage ROS induced and percentage apoptotic death. There was a positive correlation between the concentration of drug and cell death in DU-145 and PC-3 prostate cancer cells. Conclusion: The overlap in mechanisms of action of 3-BPA and SC-514 increased the impact of SC-514 on prostate cancer cells. Hence, the combination of 3-BPA and SC-514 was more therapeutically effective (synergistic effect) than the single treatments of either 3-BPA or SC-514. The synergistic effect between 3-BPA and SC-514 did not occur by ROS induction.The apoptotic induction in DU-145 and PC-3 prostate cancer cells appears to occur via a mechanism other than reactive species (ROS) induction. This study suggests that the combination of 3-BPA and SC-514 as a therapeutic regimen can inhibit prostate cancer carcinogenesis effectively.

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“…As one such therapeutic agent, 3-bromopyruvate (3BP) inhibits glycolysis, consequently limiting energy supply to tumor cells and inhibiting their rapid proliferation [ 3 – 7 ]. Studies have found that 3BP enters tumor cells through monocarboxylic acid transporter 1 (MCT1) present on the cell membrane surface [ 8 , 9 ], inhibits the activity of hexokinase II bound to the outer membrane of mitochondria, and consequently limits energy production in cells and inhibits their rapid growth [ 10 – 14 ]. Therefore, the therapeutic effect of 3BP is poor in tumor cells with low MCT1 expression [ 15 ].…”

Section: Introductionmentioning

confidence: 99%