Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells

Karim Aljakouch, Tatjana Lechtonen, Hesham K. Yosef, Mohamad K. Hammoud, Wissam Alsaidi, Carsten Kötting, Carolin Mügge, Robert Kourist, Samir F. El-Mashtoly, Klaus Gerwert

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

Tyrosine kinase receptors are one of the main targets in cancer therapy. They play an essential role in the modulation of growth factor signaling and thereby inducing cell proliferation and growth. Tyrosine kinase inhibitors such as neratinib bind to EGFR and HER2 receptors and exhibit antitumor activity. However, little is known about their detailed cellular uptake and metabolism. Here, we report for the first time the intracellular spatial distribution and metabolism of neratinib in different cancer cells using label-free Raman imaging. Two new neratinib metabolites were detected and fluorescence imaging of the same cells indicate that neratinib accumulates in lysosomes. The results also suggest that both EGFR and HER2 follow the classical endosome lysosomal pathway for degradation. A combination of Raman microscopy, DFT calculations, and LC-MS was used to identify the chemical structure of neratinib metabolites. These results show the potential of Raman microscopy to study drug pharmacokinetics.

Originalspracheenglisch
Seiten (von - bis)7250-7254
Seitenumfang5
FachzeitschriftAngewandte Chemie / International Edition
Jahrgang57
Ausgabenummer24
DOIs
PublikationsstatusVeröffentlicht - 11 Jun 2018

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Metabolites
Metabolism
Protein-Tyrosine Kinases
Microscopic examination
Cells
Imaging techniques
Pharmacokinetics
Cell proliferation
Cell growth
Discrete Fourier transforms
Spatial distribution
Labels
Fluorescence
Modulation
Degradation
Receptor Protein-Tyrosine Kinases
Intercellular Signaling Peptides and Proteins
N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
Pharmaceutical Preparations

Schlagwörter

    ASJC Scopus subject areas

    • !!Catalysis
    • !!Chemistry(all)

    Dies zitieren

    Aljakouch, K., Lechtonen, T., Yosef, H. K., Hammoud, M. K., Alsaidi, W., Kötting, C., ... Gerwert, K. (2018). Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells. Angewandte Chemie / International Edition , 57(24), 7250-7254. https://doi.org/10.1002/anie.201803394

    Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells. / Aljakouch, Karim; Lechtonen, Tatjana; Yosef, Hesham K.; Hammoud, Mohamad K.; Alsaidi, Wissam; Kötting, Carsten; Mügge, Carolin; Kourist, Robert; El-Mashtoly, Samir F.; Gerwert, Klaus.

    in: Angewandte Chemie / International Edition , Jahrgang 57, Nr. 24, 11.06.2018, S. 7250-7254.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Aljakouch, K, Lechtonen, T, Yosef, HK, Hammoud, MK, Alsaidi, W, Kötting, C, Mügge, C, Kourist, R, El-Mashtoly, SF & Gerwert, K 2018, 'Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells' Angewandte Chemie / International Edition , Jg. 57, Nr. 24, S. 7250-7254. https://doi.org/10.1002/anie.201803394
    Aljakouch, Karim ; Lechtonen, Tatjana ; Yosef, Hesham K. ; Hammoud, Mohamad K. ; Alsaidi, Wissam ; Kötting, Carsten ; Mügge, Carolin ; Kourist, Robert ; El-Mashtoly, Samir F. ; Gerwert, Klaus. / Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells. in: Angewandte Chemie / International Edition . 2018 ; Jahrgang 57, Nr. 24. S. 7250-7254.
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    abstract = "Tyrosine kinase receptors are one of the main targets in cancer therapy. They play an essential role in the modulation of growth factor signaling and thereby inducing cell proliferation and growth. Tyrosine kinase inhibitors such as neratinib bind to EGFR and HER2 receptors and exhibit antitumor activity. However, little is known about their detailed cellular uptake and metabolism. Here, we report for the first time the intracellular spatial distribution and metabolism of neratinib in different cancer cells using label-free Raman imaging. Two new neratinib metabolites were detected and fluorescence imaging of the same cells indicate that neratinib accumulates in lysosomes. The results also suggest that both EGFR and HER2 follow the classical endosome lysosomal pathway for degradation. A combination of Raman microscopy, DFT calculations, and LC-MS was used to identify the chemical structure of neratinib metabolites. These results show the potential of Raman microscopy to study drug pharmacokinetics.",
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    AU - Hammoud, Mohamad K.

    AU - Alsaidi, Wissam

    AU - Kötting, Carsten

    AU - Mügge, Carolin

    AU - Kourist, Robert

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