In vivo efficacy of the diuretic agent ethacrynic acid against multiple myeloma

Kim, Young; Gast, Sanna-Marie; Endo, Tomoyuki; Lu, Desheng; Carson, Dennis A.; Schmidt‐Wolf, Ingo G.H.

doi:10.1016/j.leukres.2012.01.025

Cited by 20 publications

(16 citation statements)

References 6 publications

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“…Bone marrow stromal cells were shown to provide Wnt ligands encouraging an exaggerated proliferation of MM cells (37)(38)(39). The inhibition of Wnt/βcatenin signaling, in return, retards MM growth as evidenced by numerous in vitro and in vivo studies (40).…”

Section: Discussionmentioning

confidence: 99%

Griseofulvin Efficiently Induces Apoptosis in In Vitro Treatment of Lymphoma and Multiple Myeloma

SCHMEEL¹,

SCHMEEL²,

KIM³

et al. 2017

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Background/Aim: Recent innovations in the development of systemic and targeted therapies have improved survival and quality of life in multiple myeloma (MM) patients. However, in most cases, this hematological malignancy of monoclonal B-lymphocytes remains incurable. Exaggerated Wnt/β-catenin signaling has been demonstrated in lymphoma and MM, therefore targeting related signaling molecules might represent a promising therapy approach.Griseofulvin, a widely used antifungal drug, is chemically related to other known Wnt-inhibitors and we recently demonstrated its potent in vivo efficacy in a murine myeloma model. Materials and Methods: The anti-tumor apoptotic effect of griseofulvin at doses ranging from 0.1-200 μM was investigated on a total of ten human and two murine myeloma/lymphoma cell lines, as determined by 3'3dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry. Results: Griseofulvin significantly induced apoptosis in all investigated myeloma and lymphoma cell lines in a dose-dependent manner, while healthy control cells were less sensitive. Conclusion: Given the known safety profile and apoptosis induction at low effective doses, our data warrant further in vitro and in vivo studies utilizing griseofulvin as a potential therapy agent for MM and lymphoma.

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Section: Discussionmentioning

confidence: 99%

Griseofulvin Efficiently Induces Apoptosis in In Vitro Treatment of Lymphoma and Multiple Myeloma

SCHMEEL¹,

SCHMEEL²,

KIM³

et al. 2017

Self Cite

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“…To evaluate whether combined treatment with EA and either afatinib or neratinib had stronger anti-tumor effects in vivo , 4T1 breast cancer cells were implanted subcutaneously into the back of syngeneic Balb/c mice. When all these tumors reached 62.5mm 3 in volume at least, mice were treated with afatinib (20 mg/kg) or neratinib (20 mg/kg) alone or together with EA (250 ug/day) for 3 weeks [ 16 ], [ 17 ], [ 18 ]. Consistent with our in vitro results, monotherapy with afatinib or neratinib decreased tumor growth, but treatment with the combination of afatinib or neratinib and EA led to marked tumor shrinkage.…”

Section: Resultsmentioning

confidence: 99%

Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

Liu

Huang

et al. 2016

Oncotarget

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Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.

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“…It also alters the expression of the Wnt target genes cyclin-D1, fibronectin and crucial proteins of the Wnt pathway. The cytotoxic mechanism of EA was revealed in a study by , where EA inhibited the Top Flash reporter (TCF/LEF) construct in a dose -dependent manner and was further demonstrated by co-immunoprecipitation studies to target LEF-1, destabilize formation of its complex with β-catenin and consequently inhibiting the Wnt pathway [21] . In a previous study we showed that EA caused a dose-dependent decline in the expression of three Wnt target genes, LEF-1, cyclin D1 and fibronectin, reflecting EA inhibition of Wnt/β-catenin signaling in chronic lymphocytic leukemia cells [5] .…”

Section: Discussionmentioning

confidence: 99%

“…In humans the maximum dose of EA when administered by intravenous injection is 100 mg/day, which results in plasma levels of around 30 µM [22] . This corresponds to the Wnt inhibitory doses used in the in vitro myeloma studies [21,23] . In mice, the oral dose of 450 µg/day should result in plasma levels close to those in humans mentioned above meaning that inhibition of tumor growth may also be feasible in humans.…”

Section: Discussionmentioning

confidence: 99%

Ethacrynic Acid and Ciclopiroxolamine in Various Cancer Cells

Schmidt‐Wolf¹,

Emekwue²,

Schmidt-Wolf³

et al. 2018

IJHT

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Extensive data from both in vitro and animal studies have demonstrated the potency of a deregulated activated Wnt pathway. Herein, we report the antitumor effects of already established novel Wnt pathway inhibitors-ethacrynic acid (EA) and Ciclopiroxolamine (CIC) on various cancer cell lines using the WST-8 assay. Our results demonstrate the significant cytotoxic potency of EA and CIC in vitro and display their strong efficacy on various tumor cells. Of particular interest, colon cancer was the most significantly affected by both drugs of all the tumor types tested in this study. This study provides a strategy for targeting Wnt-driven cancers and highlights those cancers that show a higher susceptibility to the cytotoxic effects of the Wnt inhibitors as potential candidates for further study.

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In vivo efficacy of the diuretic agent ethacrynic acid against multiple myeloma

Cited by 20 publications

References 6 publications

Griseofulvin Efficiently Induces Apoptosis in In Vitro Treatment of Lymphoma and Multiple Myeloma

Griseofulvin Efficiently Induces Apoptosis in In Vitro Treatment of Lymphoma and Multiple Myeloma

Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

Ethacrynic Acid and Ciclopiroxolamine in Various Cancer Cells

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