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Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?

Lung and colorectal cancers are among the leading causes of death from cancer worldwide. Although topotecan (TPT), a topoisomerase1 inhibitor, is a first- and second-line drug for lung and colon cancers, the development of drug resistance and toxicity still remain as a major obstacle to chemotherape...

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Autores principales: Lozon, Lama, Saleh, Ekram, Menon, Varsha, Ramadan, Wafaa S., Amin, Amr, El-Awady, Raafat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9479137/
https://www.ncbi.nlm.nih.gov/pubmed/36120345
http://dx.doi.org/10.3389/fphar.2022.938471
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author Lozon, Lama
Saleh, Ekram
Menon, Varsha
Ramadan, Wafaa S.
Amin, Amr
El-Awady, Raafat
author_facet Lozon, Lama
Saleh, Ekram
Menon, Varsha
Ramadan, Wafaa S.
Amin, Amr
El-Awady, Raafat
author_sort Lozon, Lama
collection PubMed
description Lung and colorectal cancers are among the leading causes of death from cancer worldwide. Although topotecan (TPT), a topoisomerase1 inhibitor, is a first- and second-line drug for lung and colon cancers, the development of drug resistance and toxicity still remain as a major obstacle to chemotherapeutic success. Accumulating evidence indicates increased efficacy and reduced toxicity of chemotherapeutic agents upon combining them with natural products. We aimed to investigate the possible interaction of safranal (SAF), a natural compound obtained from Crocus sativus stigma, with TPT when used in different sequences in colon and lung cancer cell lines. The growth inhibitory effect of the proposed combination given in different sequences was assessed using the colony formation assay. The comet assay, cell cycle distribution, Annexin-V staining, and expression of proteins involved in DNA damage/repair were utilized to understand the mechanism underlying the effect of the combination. SAF enhanced the growth inhibitory effects of TPT particularly when it was added to the cells prior to TPT. This combination increased the double-strand break induction and dysregulated the DNA repair machinery, particularly the tyrosyl-DNA phosphodiesterase 1 enzyme. In addition, the SAF + TPT combination increased the fraction of cells arrested at the G2/M checkpoint as well as enhanced the induction of apoptosis. The current study highlights the status of SAF as a natural product sensitizing the lung and colon cancer cells to the cytotoxic effects of the anticancer drug TPT. In addition, it emphasizes the importance of sequence-dependent interaction which can affect the overall outcome.
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spelling pubmed-94791372022-09-17 Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter? Lozon, Lama Saleh, Ekram Menon, Varsha Ramadan, Wafaa S. Amin, Amr El-Awady, Raafat Front Pharmacol Pharmacology Lung and colorectal cancers are among the leading causes of death from cancer worldwide. Although topotecan (TPT), a topoisomerase1 inhibitor, is a first- and second-line drug for lung and colon cancers, the development of drug resistance and toxicity still remain as a major obstacle to chemotherapeutic success. Accumulating evidence indicates increased efficacy and reduced toxicity of chemotherapeutic agents upon combining them with natural products. We aimed to investigate the possible interaction of safranal (SAF), a natural compound obtained from Crocus sativus stigma, with TPT when used in different sequences in colon and lung cancer cell lines. The growth inhibitory effect of the proposed combination given in different sequences was assessed using the colony formation assay. The comet assay, cell cycle distribution, Annexin-V staining, and expression of proteins involved in DNA damage/repair were utilized to understand the mechanism underlying the effect of the combination. SAF enhanced the growth inhibitory effects of TPT particularly when it was added to the cells prior to TPT. This combination increased the double-strand break induction and dysregulated the DNA repair machinery, particularly the tyrosyl-DNA phosphodiesterase 1 enzyme. In addition, the SAF + TPT combination increased the fraction of cells arrested at the G2/M checkpoint as well as enhanced the induction of apoptosis. The current study highlights the status of SAF as a natural product sensitizing the lung and colon cancer cells to the cytotoxic effects of the anticancer drug TPT. In addition, it emphasizes the importance of sequence-dependent interaction which can affect the overall outcome. Frontiers Media S.A. 2022-09-02 /pmc/articles/PMC9479137/ /pubmed/36120345 http://dx.doi.org/10.3389/fphar.2022.938471 Text en Copyright © 2022 Lozon, Saleh, Menon, Ramadan, Amin and El-Awady. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Lozon, Lama
Saleh, Ekram
Menon, Varsha
Ramadan, Wafaa S.
Amin, Amr
El-Awady, Raafat
Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?
title Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?
title_full Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?
title_fullStr Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?
title_full_unstemmed Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?
title_short Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?
title_sort effect of safranal on the response of cancer cells to topoisomerase i inhibitors: does sequence matter?
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9479137/
https://www.ncbi.nlm.nih.gov/pubmed/36120345
http://dx.doi.org/10.3389/fphar.2022.938471
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