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Article

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

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Department of Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland
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Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, 44-100 Gliwice, Poland
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Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland
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Department of Medical Biochemistry, Wroclaw Medical University, 50-367 Wroclaw, Poland
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Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
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Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary
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Institute of Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
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Department and Clinic of Internal Medicine, Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, 50-367 Wroclaw, Poland
*
Authors to whom correspondence should be addressed.
Academic Editor: Andrzej Kutner
Int. J. Mol. Sci. 2021, 22(4), 1748; https://doi.org/10.3390/ijms22041748
Received: 8 January 2021 / Revised: 3 February 2021 / Accepted: 4 February 2021 / Published: 9 February 2021
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. View Full-Text
Keywords: glycoconjugates; methotrexate; cancer treatment; glucose metabolism; drug design and discovery; anticancer drugs; targeted therapy; Warburg effect glycoconjugates; methotrexate; cancer treatment; glucose metabolism; drug design and discovery; anticancer drugs; targeted therapy; Warburg effect
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MDPI and ACS Style

Woźniak, M.; Pastuch-Gawołek, G.; Makuch, S.; Wiśniewski, J.; Krenács, T.; Hamar, P.; Gamian, A.; Szeja, W.; Szkudlarek, D.; Krawczyk, M.; Agrawal, S. In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment. Int. J. Mol. Sci. 2021, 22, 1748. https://doi.org/10.3390/ijms22041748

AMA Style

Woźniak M, Pastuch-Gawołek G, Makuch S, Wiśniewski J, Krenács T, Hamar P, Gamian A, Szeja W, Szkudlarek D, Krawczyk M, Agrawal S. In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment. International Journal of Molecular Sciences. 2021; 22(4):1748. https://doi.org/10.3390/ijms22041748

Chicago/Turabian Style

Woźniak, Marta, Gabriela Pastuch-Gawołek, Sebastian Makuch, Jerzy Wiśniewski, Tibor Krenács, Peter Hamar, Andrzej Gamian, Wiesław Szeja, Danuta Szkudlarek, Monika Krawczyk, and Siddarth Agrawal. 2021. "In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment" International Journal of Molecular Sciences 22, no. 4: 1748. https://doi.org/10.3390/ijms22041748

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