iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is one of the few chemotherapeutic drugs able to exert both cytotoxic and pro-immunogenic effects against cancer cells. Following the drug administration, the intracellular protein calreticulin is translocated with an unk...

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Main Authors: Ghigo Dario, Matera Lina, Gazzano Elena, Brusa Davide, Kopecka Joanna, De Boo Sara, Bosia Amalia, Riganti Chiara
Format: Article
Language:English
Published: BMC 2009-11-01
Series:Molecular Cancer
Online Access:http://www.molecular-cancer.com/content/8/1/108
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spelling doaj-a30d193584754f4e8f73f21d065d7dba2020-11-24T21:51:16ZengBMCMolecular Cancer1476-45982009-11-018110810.1186/1476-4598-8-108iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cellsGhigo DarioMatera LinaGazzano ElenaBrusa DavideKopecka JoannaDe Boo SaraBosia AmaliaRiganti Chiara<p>Abstract</p> <p>Background</p> <p>Doxorubicin is one of the few chemotherapeutic drugs able to exert both cytotoxic and pro-immunogenic effects against cancer cells. Following the drug administration, the intracellular protein calreticulin is translocated with an unknown mechanism onto the plasma membrane, where it triggers the phagocytosis of tumour cells by dendritic cells. Moreover doxorubicin up-regulates the inducible nitric oxide (NO) synthase (iNOS) gene in cancer cells, leading to huge amounts of NO, which in turn acts as a mediator of the drug toxicity and as a chemosensitizer agent in colon cancer. Indeed by nitrating tyrosine on the multidrug resistance related protein 3, NO decreases the doxorubicin efflux from tumour cells and enhances the drug toxicity. It is not clear if NO, beside playing a role in chemosensitivity, may also play a role in doxorubicin pro-immunogenic effects. To clarify this issue, we compared the doxorubicin-sensitive human colon cancer HT29 cells with the drug-resistant HT29-dx cells and the HT29 cells silenced for <it>iNOS </it>(HT29 <it>iNOS</it><sup>-</sup>).</p> <p>Results</p> <p>In both HT29-dx and HT29 <it>iNOS</it><sup>- </sup>cells, doxorubicin did not induce NO synthesis, had a lower intracellular accumulation and a lower toxicity. Moreover the drug failed to promote the translocation of calreticulin and the phagocytosis of HT29-dx and HT29 <it>iNOS</it><sup>-</sup>cells, which resulted both chemoresistant and immunoresistant. However, if NO levels were exogenously increased by sodium nitroprusside, the chemosensitivity to doxorubicin was restored in HT29 <it>iNOS</it><sup>-</sup>cells. In parallel the NO donor per se was sufficient to induce the exposure of calreticulin and to increase the phagocytosis of HT29 <it>iNOS</it><sup>- </sup>cells by DCs and their functional maturation, thus mimicking the pro-immunogenic effects exerted by doxorubicin in the parental drug-sensitive HT29 cells.</p> <p>Conclusion</p> <p>Our data suggest that chemo- and immuno-resistance to anthracyclines are associated in colon cancer cells and rely on a common mechanism, that is the inability of doxorubicin to induce <it>iNOS</it>. Therefore NO donors might represent a promising strategy to restore both chemosensitivity and immunosensitivity to doxorubicin in resistant cells.</p> http://www.molecular-cancer.com/content/8/1/108
collection DOAJ
language English
format Article
sources DOAJ
author Ghigo Dario
Matera Lina
Gazzano Elena
Brusa Davide
Kopecka Joanna
De Boo Sara
Bosia Amalia
Riganti Chiara
spellingShingle Ghigo Dario
Matera Lina
Gazzano Elena
Brusa Davide
Kopecka Joanna
De Boo Sara
Bosia Amalia
Riganti Chiara
iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
Molecular Cancer
author_facet Ghigo Dario
Matera Lina
Gazzano Elena
Brusa Davide
Kopecka Joanna
De Boo Sara
Bosia Amalia
Riganti Chiara
author_sort Ghigo Dario
title iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
title_short iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
title_full iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
title_fullStr iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
title_full_unstemmed iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
title_sort inos activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
publisher BMC
series Molecular Cancer
issn 1476-4598
publishDate 2009-11-01
description <p>Abstract</p> <p>Background</p> <p>Doxorubicin is one of the few chemotherapeutic drugs able to exert both cytotoxic and pro-immunogenic effects against cancer cells. Following the drug administration, the intracellular protein calreticulin is translocated with an unknown mechanism onto the plasma membrane, where it triggers the phagocytosis of tumour cells by dendritic cells. Moreover doxorubicin up-regulates the inducible nitric oxide (NO) synthase (iNOS) gene in cancer cells, leading to huge amounts of NO, which in turn acts as a mediator of the drug toxicity and as a chemosensitizer agent in colon cancer. Indeed by nitrating tyrosine on the multidrug resistance related protein 3, NO decreases the doxorubicin efflux from tumour cells and enhances the drug toxicity. It is not clear if NO, beside playing a role in chemosensitivity, may also play a role in doxorubicin pro-immunogenic effects. To clarify this issue, we compared the doxorubicin-sensitive human colon cancer HT29 cells with the drug-resistant HT29-dx cells and the HT29 cells silenced for <it>iNOS </it>(HT29 <it>iNOS</it><sup>-</sup>).</p> <p>Results</p> <p>In both HT29-dx and HT29 <it>iNOS</it><sup>- </sup>cells, doxorubicin did not induce NO synthesis, had a lower intracellular accumulation and a lower toxicity. Moreover the drug failed to promote the translocation of calreticulin and the phagocytosis of HT29-dx and HT29 <it>iNOS</it><sup>-</sup>cells, which resulted both chemoresistant and immunoresistant. However, if NO levels were exogenously increased by sodium nitroprusside, the chemosensitivity to doxorubicin was restored in HT29 <it>iNOS</it><sup>-</sup>cells. In parallel the NO donor per se was sufficient to induce the exposure of calreticulin and to increase the phagocytosis of HT29 <it>iNOS</it><sup>- </sup>cells by DCs and their functional maturation, thus mimicking the pro-immunogenic effects exerted by doxorubicin in the parental drug-sensitive HT29 cells.</p> <p>Conclusion</p> <p>Our data suggest that chemo- and immuno-resistance to anthracyclines are associated in colon cancer cells and rely on a common mechanism, that is the inability of doxorubicin to induce <it>iNOS</it>. Therefore NO donors might represent a promising strategy to restore both chemosensitivity and immunosensitivity to doxorubicin in resistant cells.</p>
url http://www.molecular-cancer.com/content/8/1/108
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