Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Selective Cytotoxic Activity and DNA Damage by an Epoxyalkyl Galactopyranoside

Estefanía Burgos-Morón
,
Nuria Pastor
,
Manuel Luis Orta
,
Julio José Jiménez-Alonso
,
Margarita Vega-Holm
ORCID logo ,
José Manuel Vega-Pérez
,
Fernando Iglesias-Guerra
,
Santiago Mateos
,
Miguel Lopez-Lazaro
ORCID logo ,
José Manuel Calderón-Montaño
* ORCID logo
Version 1 : Received: 26 April 2018 / Approved: 27 April 2018 / Online: 27 April 2018 (14:00:47 CEST)

A peer-reviewed article of this Preprint also exists.

Burgos-Morón, E.; Pastor, N.; Orta, M. L.; Jiménez-Alonso, J. J.; Vega-Holm, M.; Vega-Pérez, J. M.; Iglesias-Guerra, F.; Mateos, S.; López-Lázaro, M.; Calderón-Montaño, J. M. Selective Cytotoxic Activity and DNA Damage by an Epoxyalkyl Galactopyranoside. Drug Development Research, 2018, 79, 426–436. https://doi.org/10.1002/ddr.21483. Burgos-Morón, E.; Pastor, N.; Orta, M. L.; Jiménez-Alonso, J. J.; Vega-Holm, M.; Vega-Pérez, J. M.; Iglesias-Guerra, F.; Mateos, S.; López-Lázaro, M.; Calderón-Montaño, J. M. Selective Cytotoxic Activity and DNA Damage by an Epoxyalkyl Galactopyranoside. Drug Development Research, 2018, 79, 426–436. https://doi.org/10.1002/ddr.21483.

Abstract

Several clinically useful anticancer drugs selectively kill cancer cells by inducing DNA damage; the genomic instability and DNA repair defects of cancer cells make them more vulnerable than normal cells to the cytotoxicity of DNA-damaging agents. Because epoxide-containing compounds can induce DNA damage, we have used the MTT assay to evaluate the selective cytotoxicity of three epoxyalkyl galactopyranosides against A549 lung cancer cells and MRC-5 lung normal cells. Compound (2S,3S)-2,3-Epoxydecyl 4,6-O-(S)-benzylidene-β-D-galactopyranoside (EDBGP) showed the highest selective anticancer activity and was selected for mechanistic studies. After observing that EDBGP induced cellular DNA damage (comet assay), we found that cells deficient in nucleotide excision repair were hypersensitive to the cytotoxicity of this compound; this suggests that EDBGP may induce bulky DNA adducts. EDBGP did not inhibit glycolysis (glucose consumption and lactate production). Pre-treatment of lung cancer cells with several antioxidants did not reduce the cytotoxicity of EDBGP, thereby indicating that reactive oxygen species do not participate in the anticancer activity of this compound. Finally, EDBGP was screened against a panel of cancer cells and normal cells from several tissues, including three genetically modified skin fibroblasts with increasing degree of malignancy. Our results suggest that epoxyalkyl galactopyranosides are promising lead compounds for the development of new anticancer agents.

Keywords

epoxide, cancer, anticancer, cytotoxicity, nucleotide excision repair

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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