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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-7916191 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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