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Vitamin K3 thio-derivative: a novel specific apoptotic inducer in the doxorubicin-sensitive and -resistant cancer cells

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Summary

Vitamin K3, also known as menadione, is a synthetic lipid-soluble 2-methyl-1,4- naphthoquinone analogs of vitamin K. The vitamin K derivatives exhibit potent cytotoxicity against several cancer cell lines through ROS induction and mitochondrial dysfunction. We investigated vitamin K3-inspired derivatives as potential apoptotic inducers and analyzed their mechanisms beyond apoptosis. The cytotoxicity of a panel of vitamin K3 analogs was screened against 10 doxorubicin-sensitive and -resistant cancer cell lines overexpressing ATP-binding cassette transporters (P-glycoprotein, ABCB5, BCRP) or oncogenes (ΔEGFR) or with knockout of tumor suppressors (p53), Cell cycle arrest, apoptosis, cell migration, and microtubule formation were further investigated. The online tool SwissTargetPrediction was utilized for target prediction. Among the screened compounds, one vitamin K3 thio-derivative (No. 45, VKT-1) exhibited the most potent cytotoxicity specifically against both drug-sensitive and -resistant cancer cell lines. In addition, VKT-1 arrested the cells at the G2/M phase and induced apoptosis as detected by flow cytometry. As predicted by SwissTargetPrediction, VKT-1 targeted microtubule-associated tau protein. Indeed, VKT-1 dramatically inhibited cell migration and microtubule formation in vitro. In conclusion, the synthetic vitamin K3 thio-derivative (VKT-1) inhibited doxorubicin-sensitive and -resistant tumor cells by cell arrest, apoptosis induction, as well as, migration inhibition, and microtubule deterioration of U2OS-GFP-α-tubulin cells.

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Abbreviations

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

DMEM:

Dulbecco’s modified Eagle’s medium

RPMI-1640:

Roswell Park Memorial Institute medium; fluorescein isothiocyanate

ELISA:

Enzyme−linked immunosorbent assay

IC50 :

50% inhibition concentration

MDR:

Multidrug resistance

PBS:

Phosphate buffer saline

PI:

Propidium iodide

RNase A:

Ribonuclease A from bovine pancreas

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Acknowledgments

Prof. Mohamed Hegazy gratefully acknowledges the financial support from Alexander von Humboldt Foundation “Georg Foster Research Fellowship for Experienced Researcher” and Ge Yan thanks the support from China Scholarship Council (CSC). We are thankful for the Ph.D. stipend provided to Mona Dawood by the Ministry of Higher Education and Scientific Research as well as the Al-Neelain University, Khartoum, Sudan.

Funding

This research was partially funded by the Alexander von Humboldt Foundation awarded to MEFH.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudingerweg 5, 55128, Mainz, Germany

    Mohamed-Elamir F. Hegazy, Mona Dawood, Ge Yan & Thomas Efferth

  2. Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza, 12622, Egypt

    Mohamed-Elamir F. Hegazy

  3. Institute of Biological Chemistry, Washington State University, Pullman, WA, 99164-6340, USA

    Masashi Fukaya

  4. MicroCombiChem GmbH, Wiesbaden, Germany

    Anette Klinger & Edmond Fleischer

  5. Department of Animal Wealth Development, Faculty of Veterinary Medicine, Zagazig University, El-Zeraa str. 114, Zagazig, 44511, Egypt

    Asmaa W. Zaglool

Authors
  1. Mohamed-Elamir F. Hegazy
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  2. Masashi Fukaya
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  3. Mona Dawood
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  4. Ge Yan
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  7. Asmaa W. Zaglool
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  8. Thomas Efferth
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Corresponding author

Correspondence to Thomas Efferth.

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Conflict of interest

Mohamed-Elamir F. Hegazy declares that he has no conflict of interest.

Masashi Fukaya declares that he has no conflict of interest.

Mona Dawood declares that she has no conflict of interest.

Ge Yan declares that she has no conflict of interest.

Anette Klinger declares that she has no conflict of interest.

Edmond Fleischer declares that he has no conflict of interest.

Asmaa W. Zaglool declares that she has no conflict of interest.

Thomas Efferth declares that he has no conflict of interest.

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Hegazy, ME.F., Fukaya, M., Dawood, M. et al. Vitamin K3 thio-derivative: a novel specific apoptotic inducer in the doxorubicin-sensitive and -resistant cancer cells. Invest New Drugs 38, 650–661 (2020). https://doi.org/10.1007/s10637-019-00810-7

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  • DOI: https://doi.org/10.1007/s10637-019-00810-7

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