Valproate sensitizes human glioblastoma cells to 3-bromopyruvate-induced cytotoxicity

Ishiguro, Yuri; Kobayashi, Masaki; Ideno, Masaya; Narumi, Katsuya; Furugen, Ayako; Iseki, Ken

doi:10.1016/j.ijpharm.2018.08.039

Cited by 9 publications

(4 citation statements)

References 31 publications

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“…Another viewpoint indicated that the overexpression of ABC transporters (e.g., ABCB1, BCRP, and MRP2) contributed to a large amount of intracellular ATP consumption, which in turn increased the antitumor effects of 3-BrPA [112,113]. Indeed, valproate sensitized human glioblastoma T98G cells to cell death induced by 3-BrPA via the increased expression of MRP2 or BCRP that resulted in lower ATP levels compared to 3-BrPA alone treatment group [113].…”

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

confidence: 99%

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

Fan

Sun

et al. 2019

Cancers

122

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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: Antitumor Effects Of 3-brpa and The Underlying Mechanismmentioning

confidence: 99%

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

Fan

Sun

et al. 2019

Cancers

122

View full text Add to dashboard Cite

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“…This range of 3BP action may help overcome multidrug resistance consequent to drug primary action. It has been reported that valproate enhances 3BP-induced cell death of human glioblastoma cells through ATP depletion, due to MRP2 and BCRP valproate-dependent upregulation (Ishiguro et al, 2018). A recent emerging anticancer strategy consists in generating a redox imbalance in cells by promoting ROS overproduction or by inhibiting antioxidant systems activities.…”

Section: Discussionmentioning

confidence: 99%

The efficacy of the anticancer 3-bromopyruvate is potentiated by antimycin and menadione by unbalancing mitochondrial ROS production and disposal in U118 glioblastoma cells

Petricciuolo

Davidescu

Fettucciari

et al. 2020

Heliyon

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Metabolic reprogramming of tumour cells sustains cancer progression. Similar to other cancer cells, glioblastoma cells exhibit an increased glycolytic flow, which encourages the use of antiglycolytics as an effective complementary therapy. We used the antiglycolytic 3-bromopyruvate (3BP) as a metabolic modifier to treat U118 glioblastoma cells and investigated the toxic effects and the conditions to increase drug effectiveness at the lowest concentration. Cellular vitality was not affected by 3BP concentrations lower than 40 μM, although p-Akt dephosphorylation, p53 degradation, and ATP reduction occurred already at 30 μM 3BP. ROS generated in mitochondria were enhanced at 30 μM 3BP, possibly by unbalancing their generation and their disposal because of glutathione peroxidase inhibition. ROS triggered JNK and ERK phosphorylation, and cyt c release outside mitochondria, not accompanied by caspases-9 and -3 activation, probably due to 3BP-dependent alkylation of cysteine residues at caspase-9 catalytic site. To explore the possibility of sensitizing cells to 3BP treatment, we exploited 3BP effects on mitochondria by using 30 μM 3BP in association with antimycin A or menadione concentrations that in themselves exhibit poor toxicity. 3BP effect on cyt c release and cell vitality loss was potentiated due the greater oxidative stress induced by antimycin or menadione association with 3BP, supporting a preeminent role of mitochondrial ROS in 3BP toxicity. Indeed, the scavenger of mitochondrial superoxide MitoTEMPO counteracted 3BP-induced cyt c release and weakened the potentiating effect of 3BP/antimycin association. In conclusion, the biochemical mechanisms leading U118 glioblastoma cells to viability loss following 3BP treatment rely on mitochondrial ROS-dependent pathways. Their potentiation at low 3BP concentrations is consistent with the goal to minimize the toxic effect of the drug towards non-cancer cells.

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“…Besides, another study showed that small‐molecule inhibitors of HK2, like 3‐bromopyruvate, suppressed the cancer in high‐grade meningiomas 150 . There are also preclinical studies using agent 3‐BrPA for GBM treatment 156,157 and combined with different agents 158 . HK2 inhibition may enhance the effect of anticancer treatments; HK2 inhibition combined with radiation and temozolomide (TMZ) is a promising therapeutic strategy for increasing GBM treatment efficiency 159 .…”

Section: New Perspectives On Meningioma Treatmentmentioning

confidence: 99%

“…150 There are also preclinical studies using agent 3-BrPA for GBM treatment 156,157 and combined with different agents. 158 HK2 inhibition may enhance the effect of anticancer treatments; HK2 inhibition combined with radiation and temozolomide (TMZ) is a promising therapeutic strategy for increasing GBM treatment efficiency. 159 As a result of the publications showing that HK2 inhibitors are effective in GBM, it has been suggested that they may also be effective in other brain tumors.…”

Section: Targeting Glycolysis Pathway In Meningiomamentioning

confidence: 99%

Related mechanisms, current treatments, and new perspectives in meningioma

Inetas‐Yengin,

Bayrak

2024

Genes Chromosomes & Cancer

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Meningiomas are non‐glial tumors that are the most common primary brain tumors in adults. Although meningioma can possibly be cured with surgical excision, variations in atypical/anaplastic meningioma have a high recurrence rate and a poor prognosis. As a result, it is critical to develop novel therapeutic options for high‐grade meningiomas. This review highlights the current histology of meningiomas, prevalent genetic and molecular changes, and the most extensively researched signaling pathways and therapies in meningiomas. It also reviews current clinical studies and novel meningioma treatments, including immunotherapy, microRNAs, cancer stem cell methods, and targeted interventions within the glycolysis pathway. Through the examination of the complex landscape of meningioma biology and the highlighting of promising therapeutic pathways, this review opens the way for future research efforts aimed at improving patient outcomes in this prevalent intracranial tumor entity.

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Valproate sensitizes human glioblastoma cells to 3-bromopyruvate-induced cytotoxicity

Cited by 9 publications

References 31 publications

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

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

The efficacy of the anticancer 3-bromopyruvate is potentiated by antimycin and menadione by unbalancing mitochondrial ROS production and disposal in U118 glioblastoma cells

Related mechanisms, current treatments, and new perspectives in meningioma

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