The combined effect of dichloroacetate and 3-bromopyruvate on glucose metabolism in colorectal cancer cell line, HT-29; the mitochondrial pathway apoptosis

Nikravesh, Hojatolla; Khodayar, Mohammad Javad; Behmanesh, Babak; Mahdavinia, Masoud; Teimoori, Ali; Alboghobeish, Soheila; Zeidooni, Leila

doi:10.1186/s12885-021-08564-3

Cited by 10 publications

(5 citation statements)

References 34 publications

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“…A study by Chen et al, [ 44 ] demonstrated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) linked apoptosis in human breast cancer cells. In addition, yet another study by Nikravesh et al, [ 48 ] reported that the 3BP treatment significantly induced apoptosis, activation of caspase 3 activity, depolarization of mitochondrial membrane potential and ROS production in colorectal cancer cell line.…”

Section: Resultsmentioning

confidence: 99%

ROS mediated anticandidal efficacy of 3-Bromopyruvate prevents vulvovaginal candidiasis in mice model

Jothi,

Hong,

Enkhtsatsral

et al. 2023

PLoS ONE

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Candidal infections, particularly vulvovaginal candidiasis (VVC), necessitate effective therapeutic interventions in clinical settings owing to their intricate clinical nature and elusive understanding of their etiological mechanisms. Given the challenges in developing effective antifungal therapies, the strategy of repurposing existing pharmaceuticals has emerged as a promising approach to combat drug-resistant fungi. In this regard, the current study investigates molecular insights on the anti-candidal efficacy of a well-proven anticancer small molecule -3-bromopyruvate (3BP) against three clinically significant VVC causing Candida species viz., C. albicans, C. tropicalis and C. glabrata. Furthermore, the study validates 3BP’s therapeutic application by developing it as a vaginal cream for the treatment of VVC. 3BP exhibited phenomenal antifungal efficacy (killing >99%) with minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC) of 256 μg/mL against all tested Candida spp. Time killing kinetics experiment revealed 20 min as the minimum time required for 3BP at 2XMIC to achieve complete-killing (99.9%) in all Candida strains. Moreover, the ergosterol or sorbitol experiment explicated that the antifungal activity of 3BP does not stem from targeting the cell wall or the membrane component ergosterol. Instead, 3BP was observed to instigate a sequence of pre-apoptotic cascade events, such as phosphatidylserine (PS) externalization, nuclear condensation and ROS accumulations, as evidenced by PI, DAPI and DCFH-DA staining methods. Furthermore, 3BP demonstrated a remarkable efficacy in eradicating mature biofilms of Candida spp., achieving a maximum eradication level of 90%. Toxicity/safety profiling in both in vitro erythrocyte lysis and in vivo Galleria mellonella survival assay authenticated the non-toxic nature of 3BP up to 512 μg/mL. Finally, a vaginal cream formulated with 3BP was found to be effective in VVC-induced female mice model, as it significantly decreasing fungal load and protecting vaginal mucosa. Concomitantly, the present study serves as a clear demonstration of antifungal mechanistic action of anticancer drug -3BP, against Candida species. This finding holds significant potential for mitigating candidal infections, particularly VVC, within healthcare environments.

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Section: Resultsmentioning

confidence: 99%

ROS mediated anticandidal efficacy of 3-Bromopyruvate prevents vulvovaginal candidiasis in mice model

Jothi,

Hong,

Enkhtsatsral

et al. 2023

PLoS ONE

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“…Synergism has been reported when DCA is combined with different drugs for anti-cancer research: DCA/cisplatin or gefitnib or elotinib ( Al-Azawi et al, 2021 ), DCA/metformin ( Kim et al, 2021 ; Klose et al, 2021 ; Korsakova et al, 2021 ), DCA/3-bromopyruvate ( Nikravesh et al, 2021 ), DCA/sorafenib ( Sun et al, 2021 ), DCA/PX-478 ( Parczyk et al, 2021 ) and DCA/erlotinib ( Dyrstad et al, 2021 ). Said synergistic effect has also been observed when Nic is combined with other agents: Nic/gemcitabine ( Guo et al, 2022b ), Nic/metformin ( Kang et al, 2021 ) and Nic/doxorubicin ( Lohiya and Katti, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…DCA has been shown to elevate hydrogen peroxide ( Xie et al, 2011 ) and ROS ( Kumar et al, 2012 ; Duan et al, 2013 ; Kim et al, 2021 ; Klose et al, 2021 ; Nikravesh et al, 2021 ). In addition, ROS is increased when DCA is combined with sorafenib ( Sun et al, 2021 ) or PX-478 ( Parczyk et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

et al. 2022

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Background: Inhalation of asbestos fibers is the most common cause of malignant pleural mesothelioma (MPM). In 2004, the United States Food and Drug Administration approved a combination of cisplatin with pemetrexed to treat unresectable MPM. Nonetheless novel treatment is urgently needed. The objective of this study is to report the combination effect of dichloroacetate (DCA) or niclosamide (Nic) Nic in MPM.Materials and methods: The effect of a combination of DCA and Nic was studied using a panel of MPM cell lines (H28, MSTO-211H, H226, H2052, and H2452). Cell viability was monitored by MTT assay. Glycolysis, oxidative phosphorylation, glucose, glycogen, pyruvate, lactate, citrate, succinate and ATP levels were determined by corresponding ELISA. Apoptosis, mitochondrial transmembrane potential, cell cycle analysis, hydrogen peroxide and superoxide were investigated by flow cytometry. Cell migration and colony formation were investigated by transwell migration and colony formation assays respectively. The in vivo effect was confirmed using 211H and H226 nude mice xenograft models.Results and conclusion: Cell viability was reduced. Disturbance of glycolysis and/or oxidative phosphorylation resulted in downregulation of glycogen, citrate and succinate. DCA and/or Nic increased apoptosis, mitochondrial transmembrane depolarization, G2/M arrest and reactive oxygen species. Moreover, DCA and/or Nic suppressed cell migration and colony formation. Furthermore, a better initial tumor suppressive effect was induced by the DCA/Nic combination compared with either drug alone in both 211H and H226 xenograft models. In H226 xenografts, DCA/Nic increased median survival of mice compared with single treatment. Single drug and/or a combination disturbed the Warburg effect and activated apoptosis, and inhibition of migration and proliferation in vivo. In conclusion, dichloroacetate and/or niclosamide showed a tumor suppressive effect in MPM in vitro and in vivo, partially mediated by disturbance of glycolysis/oxidative phosphorylation, apoptosis, ROS production, G2/M arrest, and suppression of migration and proliferation.

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“…3-BrPA is an analog of pyruvate with high tumor selectivity ( 28 ). This small alkylating compound can induce cell death through two mechanisms: One involves inhibiting HK2 to prevent the glycolysis process ( 29 ), and the other involves activating the mitochondrial pathway of apoptosis ( 30 ). 3-BrPA functions in a variety of tumor cells, including multiple myeloma cells ( 31 ) and hepatocellular carcinoma cells ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

3‑Bromopyruvic acid regulates glucose metabolism by targeting the c‑Myc/TXNIP axis and induces mitochondria‑mediated apoptosis in TNBC cells

Pan

Liu

et al. 2022

Exp Ther Med

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Aerobic glycolysis is commonly observed in tumor cells, including triple-negative breast cancer (TNBC) cells, and the rate of aerobic glycolysis is higher in TNBC cells than in non-TNBC cells. Hexokinase 2 (HK2) is a key enzyme in the glycolytic pathway and a target of the transcription factor c-Myc, which is highly expressed in TNBC and promotes aerobic glycolysis by enhancing HK2 expression. As an inhibitor of HK2, 3-bromopyruvic acid (3-BrPA) exhibits good therapeutic efficacy in intrahepatic and extrahepatic tumors and inhibits the proliferation of human tumor cells with high expression levels of c-Myc in vivo and in vitro . In addition, 3-BrPA combines with photodynamic therapy to inhibit TNBC cell migration. Thioredoxin-interacting protein (TXNIP) competes with c-Myc to reduce glucose consumption in tumor cells to restrain cell proliferation. A comparative analysis was performed in the present study in TNBC (HCC1143) and non-TNBC (MCF-7) cell lines to explore the effect of 3-BrPA on energy metabolism in TNBC cells and to investigate the possible mechanism of action. Cell viability and apoptosis were detected through Cell Counting Kit-8 and flow cytometry assays, respectively. Expression levels of HK2, glucose transporter 1, TXNIP, c-Myc and mitochondria-regulated apoptosis pathway proteins were measured through western blotting. 3-BrPA inhibited cell proliferation, downregulated c-Myc and HK2 expression, and upregulated TXNIP expression in TNBC cells, but it doesn't have the same effect on non-TNBC cells. Furthermore, 3-BrPA induced the typical manifestations of mitochondrial-mediated apoptosis such as decreasing Bcl-2 expression and increasing Bax, Cyt-C and Caspase-3 expression. The present results suggested that 3-BrPA promoted TXNIP protein expression and reduced HK2 expression in TNBC cells by downregulating c-Myc expression, inhibiting glycolysis including suppressing lactate generation, intracellular ATP generation and HK activity, inducing mitochondrial-mediated apoptosis and eventually suppressing TNBC cell proliferation. These findings may reveal a novel therapeutic target for the clinical treatment of TNBC.

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The combined effect of dichloroacetate and 3-bromopyruvate on glucose metabolism in colorectal cancer cell line, HT-29; the mitochondrial pathway apoptosis

Cited by 10 publications

References 34 publications

ROS mediated anticandidal efficacy of 3-Bromopyruvate prevents vulvovaginal candidiasis in mice model

ROS mediated anticandidal efficacy of 3-Bromopyruvate prevents vulvovaginal candidiasis in mice model

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

3‑Bromopyruvic acid regulates glucose metabolism by targeting the c‑Myc/TXNIP axis and induces mitochondria‑mediated apoptosis in TNBC cells

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