4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.

<h4>Background</h4>The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the pa...

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Autores principales:	Paola Tiberio, Elena Cavadini, Gabriella Abolafio, Franca Formelli, Valentina Appierto
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/29f2061d33aa4882abbe95291e36ac2a
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spelling	oai:doaj.org-article:29f2061d33aa4882abbe95291e36ac2a2021-11-18T07:03:17Z4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.1932-620310.1371/journal.pone.0013362https://doaj.org/article/29f2061d33aa4882abbe95291e36ac2a2010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20976277/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines.<h4>Methodology/principal findings</h4>We provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest.<h4>Conclusions/significance</h4>These data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance.Paola TiberioElena CavadiniGabriella AbolafioFranca FormelliValentina AppiertoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13362 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paola Tiberio Elena Cavadini Gabriella Abolafio Franca Formelli Valentina Appierto 4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
description	<h4>Background</h4>The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines.<h4>Methodology/principal findings</h4>We provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest.<h4>Conclusions/significance</h4>These data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance.
format	article
author	Paola Tiberio Elena Cavadini Gabriella Abolafio Franca Formelli Valentina Appierto
author_facet	Paola Tiberio Elena Cavadini Gabriella Abolafio Franca Formelli Valentina Appierto
author_sort	Paola Tiberio
title	4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
title_short	4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
title_full	4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
title_fullStr	4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
title_full_unstemmed	4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
title_sort	4-oxo-n-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/29f2061d33aa4882abbe95291e36ac2a
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4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.

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