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In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment

Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose–methotrexate c...

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Autores principales: Woźniak, Marta, Pastuch-Gawołek, Gabriela, Makuch, Sebastian, Wiśniewski, Jerzy, Krenács, Tibor, Hamar, Peter, Gamian, Andrzej, Szeja, Wiesław, Szkudlarek, Danuta, Krawczyk, Monika, Agrawal, Siddarth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916191/
https://www.ncbi.nlm.nih.gov/pubmed/33572433
http://dx.doi.org/10.3390/ijms22041748
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author Woźniak, Marta
Pastuch-Gawołek, Gabriela
Makuch, Sebastian
Wiśniewski, Jerzy
Krenács, Tibor
Hamar, Peter
Gamian, Andrzej
Szeja, Wiesław
Szkudlarek, Danuta
Krawczyk, Monika
Agrawal, Siddarth
author_facet Woźniak, Marta
Pastuch-Gawołek, Gabriela
Makuch, Sebastian
Wiśniewski, Jerzy
Krenács, Tibor
Hamar, Peter
Gamian, Andrzej
Szeja, Wiesław
Szkudlarek, Danuta
Krawczyk, Monika
Agrawal, Siddarth
author_sort Woźniak, Marta
collection PubMed
description Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose–methotrexate conjugate (GLU–MTX) both in vitro and in vivo, in which a cleavable linkage allows intracellular MTX release after selective uptake through glucose transporter−1 (GLUT1). GLU–MTX inhibited the growth of colorectal (DLD-1), breast (MCF-7) and lung (A427) adenocarcinomas, squamous cell carcinoma (SCC-25), osteosarcoma (MG63) cell lines, but not in WI-38 healthy fibroblasts. In tumor cells, GLU–MTX uptake increased 17-fold compared to unconjugated MTX. 4,6-O-ethylidene-α-D-glucose (EDG), a GLUT1 inhibitor, significantly interfered with GLU–MTX induced growth inhibition, suggesting a glucose-mediated drug uptake. Glu-MTX also caused significant tumor growth delay in vivo in breast cancer-bearing mice. These results show that our GLUT-MTX conjugate can be selectively uptake by a range of tumor cells to cause their significant growth inhibition in vitro, which was also confirmed in a breast cancer model in vivo. GLUT1 inhibitor EDG interfered with these effects verifying the selective drug uptake. Accordingly, GLU–MTX offers a considerable tumor selectivity and may offer cancer growth inhibition at reduced toxicity.
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spelling pubmed-79161912021-03-01 In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment Woźniak, Marta Pastuch-Gawołek, Gabriela Makuch, Sebastian Wiśniewski, Jerzy Krenács, Tibor Hamar, Peter Gamian, Andrzej Szeja, Wiesław Szkudlarek, Danuta Krawczyk, Monika Agrawal, Siddarth Int J Mol Sci Article Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose–methotrexate conjugate (GLU–MTX) both in vitro and in vivo, in which a cleavable linkage allows intracellular MTX release after selective uptake through glucose transporter−1 (GLUT1). GLU–MTX inhibited the growth of colorectal (DLD-1), breast (MCF-7) and lung (A427) adenocarcinomas, squamous cell carcinoma (SCC-25), osteosarcoma (MG63) cell lines, but not in WI-38 healthy fibroblasts. In tumor cells, GLU–MTX uptake increased 17-fold compared to unconjugated MTX. 4,6-O-ethylidene-α-D-glucose (EDG), a GLUT1 inhibitor, significantly interfered with GLU–MTX induced growth inhibition, suggesting a glucose-mediated drug uptake. Glu-MTX also caused significant tumor growth delay in vivo in breast cancer-bearing mice. These results show that our GLUT-MTX conjugate can be selectively uptake by a range of tumor cells to cause their significant growth inhibition in vitro, which was also confirmed in a breast cancer model in vivo. GLUT1 inhibitor EDG interfered with these effects verifying the selective drug uptake. Accordingly, GLU–MTX offers a considerable tumor selectivity and may offer cancer growth inhibition at reduced toxicity. MDPI 2021-02-09 /pmc/articles/PMC7916191/ /pubmed/33572433 http://dx.doi.org/10.3390/ijms22041748 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Woźniak, Marta
Pastuch-Gawołek, Gabriela
Makuch, Sebastian
Wiśniewski, Jerzy
Krenács, Tibor
Hamar, Peter
Gamian, Andrzej
Szeja, Wiesław
Szkudlarek, Danuta
Krawczyk, Monika
Agrawal, Siddarth
In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
title In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
title_full In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
title_fullStr In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
title_full_unstemmed In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
title_short In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
title_sort in vitro and in vivo efficacy of a novel glucose–methotrexate conjugate in targeted cancer treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916191/
https://www.ncbi.nlm.nih.gov/pubmed/33572433
http://dx.doi.org/10.3390/ijms22041748
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