Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis

Objective FoxM1 transcription factor contributes to tumor metastasis and poor prognosis in many cancers including triple-negative breast cancer (TNBC). In this study, we examined the effects of FoxM1 inhibitor Thiostrepton (THIO) alone or in combination with MEK inhibitor Selumetinib (SEL) on metast...

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Published in:Molecular biology reports 2022-11, Vol.49 (11), p.10387-10397
Main Authors: Demirtas Korkmaz, Funda, Dogan Turacli, Irem, Esendagli, Guldal, Ekmekci, Abdullah
Format: Article
Language:English
Subjects:
Animal Anatomy
Animal Biochemistry
Biomedical and Life Sciences
Breast cancer
Cell migration
Cell viability
Cytology
Drug delivery
E-cadherin
Histology
Immunoblotting
Immunohistochemistry
Life Sciences
MEK inhibitors
Mesenchyme
Metastases
Metastasis
Morphology
Original Article
Thiostrepton
Vimentin
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Summary:Objective FoxM1 transcription factor contributes to tumor metastasis and poor prognosis in many cancers including triple-negative breast cancer (TNBC). In this study, we examined the effects of FoxM1 inhibitor Thiostrepton (THIO) alone or in combination with MEK inhibitor Selumetinib (SEL) on metastatic parameters in vitro and in vivo. Methods Cell viability was determined by MTT assay. Immunoblotting and immunohistochemistry was used to assess metastasis-related protein expressions in 4T1 cells and its allograft tumor model in BALB/c mice. In vivo uPA activity was determined by enzymatic methods. Results Both inhibitors were effective on the expressions of FoxM1, ERK, p-ERK, Twist, E-cadherin, and Vimentin alone or in combination in vitro . THIO significantly decreased 4T1 cell migration and changed the cell morphology from mesenchymal-like to epithelial-like structure. THIO was more effective than in combination with SEL in terms of metastatic protein expressions in vivo . THIO alone significantly inhibited mean tumor growth, decreased lung metastasis rate and tumor foci, however, no significant changes in these parameters were observed in the combined group. Immunohistochemically, FoxM1 expression intensity was decreased with THIO and its combination with SEL in the tumors. Conclusions This study suggests that inhibiting FoxM1 as a single target is more effective than combined treatment with MEK in theTNBC allograft model. The therapeutic efficacy of THIO should be investigated with further studies on appropriate drug delivery systems.
ISSN:0301-4851
1573-4978
DOI:10.1007/s11033-022-07751-0