3-Bromopyruvate regulates the status of glycolysis and BCNU sensitivity in human hepatocellular carcinoma cells

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

doi:10.1016/j.bcp.2020.113988

Cited by 34 publications

(19 citation statements)

References 63 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: 88%

“…In this case, weak bases outside the cells would be transformed into the charged protonated ammonium form, which cannot be diffused into the cell [54]. LND is known to selectively cause intracellular acidification and deplete cellular energy within tumors [76]. Furthermore, LND-induced decrease of pHi was much more obvious than pHe [54], this would lead to the high uptake of weak basic DOX by tumors, which is due to the cation trapping mechanism as a result of protonation driven by the enhanced intracellular acidification [55].…”

Section: Lnd In Combination With Anthracyclinesmentioning

confidence: 99%

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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: 88%

Section: Lnd In Combination With Anthracyclinesmentioning

confidence: 99%

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

Huang

Sun

et al. 2020

Cancers

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“…3-Bromopyruvic acid (3-BrPA) functions as a potential clinical chemosensitizer to optimize the therapeutic index of chloroethylnitrosoureas, a bifunctional antitumor alkylating agent 146 . Besides the inhibition of HK2, the inhibition of GAPDH, PGK1, lactate dehydrogenase (LDH) and succinate dehydrogenase are also reported to be a part of anti-cancer activities of 3-BrPA 147 , 148 .…”

Section: Emerging Therapeutical Strategies For the Treatment Of Hccmentioning

confidence: 99%

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Liu

Qin

et al. 2022

Acta Pharmaceutica Sinica B

292

155

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“…Being an alkylating agent on HKII and other enzymes, including anti-oxidant enzymes, it has been proposed as a potential enhancer of alkylating chemotherapeutic drugs. Indeed, 3BrPyr successfully increases the sensitivity to carmustine in hepatocellular carcinoma cells, by inhibiting glycolysis and inactivating several targeting proteins involved in redox homeostasis [207]. Both HKII and PDK1, two glycolytic enzymes upregulated by HIF-1α but inhibited by wild-type TP53, cooperate in inducing chemoresistance to cisplatin in ovarian cancer, by maintaining high levels of glycolytic flux and pro-survival pathways: indeed, PDK1 activates Akt signaling that counteracts cisplatin cytotoxic effects [208].…”

Section: Counteracting Hypoxic Metabolic Rewiring: a New Generation Of Chemosensitizing Agentsmentioning

confidence: 99%

Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

Belisario

Kopecka

Pasino

et al. 2020

Cells

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Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.

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3-Bromopyruvate regulates the status of glycolysis and BCNU sensitivity in human hepatocellular carcinoma cells

Cited by 34 publications

References 63 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

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

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