Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the DNA interstrand cross-links formation

Sun, Xiaodong; Sun, Guizhi; Huang, Yaxin; Zhang, Shufen; Tang, Xiaoyu; Zhang, Na; Zhao, Lu; Zhong, Rugang; Peng, Yongzhen

doi:10.1016/j.tox.2020.152413

Cited by 17 publications

(13 citation statements)

References 33 publications

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“…For NMs alkylating agents, the mechanism of LND-induced potentiation may include (1) intracellular acid leads to increased concentration of the active aziridinium ion intermediate that yields DNA damage; (2) de-energization prevents the energy-dependent MDR pump from pumping out the drugs; (3) under acidic condition, GST activity is inhibited, leading to decreased level of GSH which can quench the active aziridinium species; and (4) reduced DNA repair due to the acid inhibition of repair protein [45,46]. In fact, this mechanism resembles the "HLAGR" mechanism recently proposed by us in the chemosensitization of carmustine (BCNU) mediated by another glycolytic inhibitor 3-bromopyruvate [76,77].…”

Section: Lnd In Combination With Nitrogen Mustardsmentioning

confidence: 89%

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

Huang

Sun

et al. 2020

Cancers

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Lonidamine (LND) has the ability to resist spermatogenesis and was first used as an anti-spermatogenic agent. Later, it was found that LND has a degree of anticancer activity. Currently, LND is known to target energy metabolism, mainly involving the inhibition of monocarboxylate transporter (MCT), mitochondrial pyruvate carrier (MPC), respiratory chain complex I/II, mitochondrial permeability transition (PT) pore, and hexokinase II (HK-II). However, phase II clinical studies showed that LND alone had a weak therapeutic effect, and the effect was short and reversible. Interestingly, LND does not have the common side effects of traditional chemotherapeutic drugs, such as alopecia and myelosuppression. In addition, LND has selective activity toward various tumors, and its toxic and side effects do not overlap when combined with other chemotherapeutic drugs. Therefore, LND is commonly used as a chemosensitizer to enhance the antitumor effects of chemotherapeutic drugs based on its disruption of energy metabolism relating to chemo- or radioresistance. In this review, we summarized the combination treatments of LND with several typical chemotherapeutic drugs and several common physical therapies, such as radiotherapy (RT), hyperthermia (HT), and photodynamic therapy (PDT), and discussed the underlying mechanisms of action. Meanwhile, the development of novel formulations of LND in recent years and the research progress of LND derivative adjudin (ADD) as an anticancer drug were also discussed.

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Section: Lnd In Combination With Nitrogen Mustardsmentioning

confidence: 89%

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

Huang

Sun

et al. 2020

Cancers

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“…In such cases, the strategy of combining energy metabolism blockers with chemotherapy is more rational. Recently, we explored the chemo-sensitization effects of two typical glycolytic inhibitors, 3-BrPA and 2-deoxy-glucose (2-DG), on human hepatocellular carcinoma and glioblastoma cells in vitro and in vivo . − These promising results prompted us to investigate the sensitizing effects of other glycolytic inhibitors, because MGMT-mediated resistance still exists in the case of 3-BrPA and 2-DG.…”

Section: Discussionmentioning

confidence: 99%

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O⁶-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

Huang,

Wang,

Fan

et al. 2024

ACS Pharmacol. Transl. Sci.

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Tumor resistance seriously hinders the clinical application of chloroethylnitrosoureas (CENUs), such as O 6methylguanine-DNA methylguanine (MGMT), which can repair O 6 -alkyl lesions, thereby inhibiting the formation of cytotoxic DNA interstrand cross-links (ICLs). Metabolic differences between tumor and normal cells provide a biochemical basis for novel therapeutic strategies aimed at selectively inhibiting tumor energy metabolism. In this study, the energy blocker lonidamine (LND) was selected as a chemo-sensitizer of nimustine (ACNU) to explore its potential effects and underlying mechanisms in human glioblastoma in vitro and in vivo. A series of cell-level studies showed that LND significantly increased the cytotoxic effects of ACNU on glioblastoma cells. Furthermore, LND plus ACNU enhanced the energy deficiency by inhibiting glycolysis and mitochondrial function. Notably, LND almost completely downregulated MGMT expression by inducing intracellular acidification. The number of lethal DNA ICLs produced by ACNU increased after the LND pretreatment. The combination of LND and ACNU aggravated cellular oxidative stress. In resistant SF763 mouse tumor xenografts, LND plus ACNU significantly inhibited tumor growth with fewer side effects than ACNU alone. Finally, we proposed a new "HMAGOMR" chemo-sensitizing mechanism through which LND may act as a potential chemo-sensitizer to reverse ACNU resistance in glioblastoma: moderate inhibition of hexokinase (HK) activity (H); mitochondrial dysfunction (M); suppressing adenosine triphosphate (ATP)-dependent drug efflux (A); changing redox homeostasis to inhibit GSH-mediated drug inactivation (G) and increasing intracellular oxidative stress (O); downregulating MGMT expression through intracellular acidification (M); and partial inhibition of energy-dependent DNA repair (R).

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“…O 6 -BG is an inhibitor of AGT that can effectively inhibit the activity of AGT. By contrast, O 6 -BTG can exert superior inhibitory effects on AGT, and has since entered clinical trial testing, but it lacks a specific target and induces serious myelosuppressive toxicity ( 83 , 84 ). Tumor cell death is dependent on the inhibition of glycolysis.…”

Section: Nitrosourea-based Chemotherapymentioning

confidence: 99%

“…The glycolysis inhibitor 3-bromopyruvate combined with BCNU has been shown to significantly enhance the cytotoxicity of BCNU while reducing intracellular ATP and glutathione levels in human glioma cell lines SF763 and SF126. Glycolysis inhibitors are expected to become an effective agent for reversing nitrosourea resistance ( 84 ). Rezaei et al ( 40 ) previously treated U373 glioma cells with microRNA (miR or miRNA)-181a combined with BCNU.…”

Section: Nitrosourea-based Chemotherapymentioning

confidence: 99%

Research progress of anti-glioma chemotherapeutic drugs (Review)

et al. 2022

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Glioma is the most common primary intracranial malignancy in the central nervous system. At present, the most important treatment option is surgical resection of the tumor combined with radiotherapy and chemotherapy. The principle of operation is to remove the tumor to the maximal extent on the basis of preserving brain function. However, prominent invasive and infiltrative proliferation of glioma tumor cells into the surrounding normal tissues frequently reduces the efficacy of treatment. This in turn worsens the prognosis, because the tumor cannot be completely removed, which can readily relapse. Chemotherapeutic agents when applied individually have demonstrated limited efficacy for the treatment of glioma. However, multiple different chemotherapeutic agents can be used in combination with other treatment modalities to improve the efficacy while circumventing systemic toxicity and drug resistance. Therefore, it is pivotal to unravel the inhibitory mechanism mediated by the different chemotherapeutic drugs on glioma cells in preclinical studies. The aim of the present review is to provide a summary for understanding the effects of different chemotherapeutic drugs in glioma, in addition to providing a reference for the preclinical research into novel chemotherapeutic agents for future clinical application.

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Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the DNA interstrand cross-links formation

Cited by 17 publications

References 33 publications

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O⁶-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

Research progress of anti-glioma chemotherapeutic drugs (Review)

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Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the DNA interstrand cross-links formation

Cited by 17 publications

References 33 publications

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O6-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation

Research progress of anti-glioma chemotherapeutic drugs (Review)

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Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O⁶-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation