Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor

Lee, Young Eun; Choi, Seung Ah; Kwack, Pil Ae; Kim, Hak Jae; Kim, Il Han; Wang, Kyu Chang; Lee, Ji Yeoun; Chong, Sangjoon; Park, Shin Young; Park, Kyung Duk; Hwang, Do Won; Joo, Kyeung Min; Kim, Seung Ki

doi:10.1093/neuonc/now300

Cited by 25 publications

(34 citation statements)

References 47 publications

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“…Normal cells are not affected by gossypol and phenformin, because the cells use mitochondrial NADH produced from the TCA cycle. Therefore, gossypol and phenformin did not affect ATP production in normal cells, or the growth of normal body weight during treatment 7 , 10 . Here we observed that irinotecan resistant NSCLC cells showed increased mitochondrial OxPhos.…”

Section: Introductionmentioning

confidence: 84%

“…Recently, we have shown that ATP production through OxPhos in NSCLC can be stalled down to 20% of the control, by combination treatment of inhibitions for aldehyde dehydrogenase (ALDH) and mitochondrial electron transfer complex I using gossypol and phenformin 7 – 9 . The suggested mechanism of ATP depletion was based on the cancer cell using cytosolic NADH produced by ALDH as an electron source for ATP synthesis through OxPhos 7 , 8 , 10 . Normal cells are not affected by gossypol and phenformin, because the cells use mitochondrial NADH produced from the TCA cycle.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Mitochondrial Oxidative Phosphorylation Abrogated Irinotecan Resistance in NSCLC

Lee

Seo

et al. 2018

Sci Rep

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Anticancer drug resistance is a major challenge of cancer therapy. We found that irinotecan-resistant NSCLC cells showed increased mitochondrial oxidative phosphorylation compared to the drug sensitive NSCLC cells. Previously, we found that combined inhibition of aldehyde dehydrogenase using gossypol, and mitochondrial complex I using phenformin, effectively reduced oxidative phosphorylation in NSCLC. Here, we showed that targeting oxidative phosphorylation with gossypol and phenformin abrogated irinotecan resistance in NSCLC. Furthermore, irinotecan treatment by blocking oxidative phosphorylation induced synergistic anti-cancer effect in NSCLC. The pre-clinical xenograft model of human NSCLC also demonstrated a therapeutic response to the dual targeting treatment. Therefore, this combination of gossypol and phenformin increases irinotecan sensitivity as well as preventing irinotecan resistance.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Targeting Mitochondrial Oxidative Phosphorylation Abrogated Irinotecan Resistance in NSCLC

Lee

Seo

et al. 2018

Sci Rep

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“…injection of 30 mg/kg zoletil (Virbac SA, France) and 10 mg/kg xylazine (Bayer Inc., Toronto, Ontario). As previously described, luciferase-expressing U87 MG (U87 MG-effluc) was used for bioluminescence imaging [54]. The cells were expanded to 90% confluence and divided into two groups.…”

Section: Orthotopic U87 Mg Xenograft Mouse Modelmentioning

confidence: 99%

“…For histological analysis, the mice were sacrificed after 44 days of the U87 MG efflux cell injection. Cardiac perfusion was performed and frozen blocks were prepared for sectioning as previously reported [54]. The tissues were stained with hematoxylin and eosin (H&E) to mark the tumor volume within the sections.…”

Section: Tumor Volume and Immunofluorescence Stainingmentioning

confidence: 99%

Non-Thermal Atmospheric Pressure Bio-Compatible Plasma Stimulates Apoptosis via p38/MAPK Mechanism in U87 Malignant Glioblastoma

Akter

Jangra

Choi

et al. 2020

Cancers

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Nonthermal plasma is a promising novel therapy for the alteration of biological and clinical functions of cells and tissues, including apoptosis and inhibition of tumor progression. This therapy generates reactive oxygen and nitrogen species (RONS), which play a major role in anticancer effects. Previous research has verified that plasma jets can selectively induce apoptosis in various cancer cells, suggesting that it could be a potentially effective novel therapy in combination with or as an alternative to conventional therapeutic methods. In this study, we determined the effects of nonthermal air soft plasma jets on a U87 MG brain cancer cell line, including the dose- and time-dependent effects and the physicochemical and biological correlation between the RONS cascade and p38/mitogen-activated protein kinase (MAPK) signaling pathway, which contribute to apoptosis. The results indicated that soft plasma jets efficiently inhibit cell proliferation and induce apoptosis in U87 MG cells but have minimal effects on astrocytes. These findings revealed that soft plasma jets produce a potent cytotoxic effect via the initiation of cell cycle arrest and apoptosis. The production of reactive oxygen species (ROS) in cells was tested, and an intracellular ROS scavenger, N-acetyl cysteine (NAC), was examined. Our results suggested that soft plasma jets could potentially be used as an effective approach for anticancer therapy.

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“…Some compounds, such as disul ram, have thiol groups, and their metal complexes have been reported to be radiosensitizers against a range of cancers due to their potential to induce oxidative stress [36]. Similar to disul ram, BAL has thiol groups and has capacity to form multiple complexes with arsenic cations.…”

Section: Discussionmentioning

confidence: 99%

A formula constituted by arsenic trioxide and dimercaprol enhances sensitivity of pancreatic cancer xenografts to radiotherapy

Han¹,

Wu²,

Liu³

et al. 2020

Preprint

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Objective To investigate the efficacy of the formula constituted by arsenic trioxide (ATO) and dimercaprol (BAL), BAL-ATO, as a radiosensitizer against pancreatic cancer xenografts. Methods Four treatment arms, including the control, radiotherapy (RT), BAL-ATO and RT + BAL-ATO, were examined using mouse models bearing SW 1990 human pancreatic cancer xenografts. Besides survival and tumor volume analysis, living imaging for cell apoptosis in tumor samples, confocal laser microscope observation for hypoxia, western blot and immunohistochemistry (IHC) assays were employed to detect the mechanism of BAL-ATO in radiotherapy. Results The median survival of the combination (RT + BAL-ATO) group (64.5 days) was significantly longer than those of the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups ( P < 0.001 ). Compared to the control group, RT + BAL-ATO inhibited the growth of tumors in mice by 73%, which was much higher than the rate of inhibition of RT alone (59%). The further analysis results also showed an improved microenvironment with regard to hypoxia in tumors treated by BAL-ATO alone or RT + BAL-ATO; besides, the suppression of signals, such as CD24, CD44, ALDH1A1, Gli-1 and Nestin, those associating with pancreatic cancer stem cells (PCSCs), were detected in the tumor samples treated by BAL-ATO alone or RT combing with BAL-ATO. Conclusion The data suggested that BAL-ATO, a formula constituted by ATO and BAL, could function as a sensitizer to radiotherapy for pancreatic cancer xenografts, and the mechanism might be attributed to hypoxia reduction and inhibition to signal pathways associated with PCSCs.

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Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor

Abstract: DSF and RT combination therapy has additive therapeutic effects on AT/RT by potentiating programmed cell death, including apoptosis and autophagy of AT/RT cells. We suggest that DSF can be applied as a radiosensitizer in AT/RT treatment.

Cited by 25 publications

References 47 publications

Targeting Mitochondrial Oxidative Phosphorylation Abrogated Irinotecan Resistance in NSCLC

Targeting Mitochondrial Oxidative Phosphorylation Abrogated Irinotecan Resistance in NSCLC

Non-Thermal Atmospheric Pressure Bio-Compatible Plasma Stimulates Apoptosis via p38/MAPK Mechanism in U87 Malignant Glioblastoma

A formula constituted by arsenic trioxide and dimercaprol enhances sensitivity of pancreatic cancer xenografts to radiotherapy

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