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Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD

One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is to provide effective penetration of drug molecules to...

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Autores principales: Fadeev, Roman, Chekanov, Alexey, Solovieva, Marina, Bezborodova, Olga, Nemtsova, Elena, Dolgikh, Nadezda, Fadeeva, Irina, Senotov, Anatoly, Kobyakova, Margarita, Evstratova, Yana, Yakubovskaya, Raisa, Akatov, Vladimir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387460/
https://www.ncbi.nlm.nih.gov/pubmed/30691192
http://dx.doi.org/10.3390/ijms20030525
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author Fadeev, Roman
Chekanov, Alexey
Solovieva, Marina
Bezborodova, Olga
Nemtsova, Elena
Dolgikh, Nadezda
Fadeeva, Irina
Senotov, Anatoly
Kobyakova, Margarita
Evstratova, Yana
Yakubovskaya, Raisa
Akatov, Vladimir
author_facet Fadeev, Roman
Chekanov, Alexey
Solovieva, Marina
Bezborodova, Olga
Nemtsova, Elena
Dolgikh, Nadezda
Fadeeva, Irina
Senotov, Anatoly
Kobyakova, Margarita
Evstratova, Yana
Yakubovskaya, Raisa
Akatov, Vladimir
author_sort Fadeev, Roman
collection PubMed
description One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is to provide effective penetration of drug molecules to cancer cells. TRAIL (TNFα-related apoptosis inducing ligand)/Apo2L is a highly selective anticancer agent. However, the recombinant TRAIL protein having high efficiency against cancer cells in vitro was not effective in clinical trials. Recently we have discovered an acquisition of TRAIL resistance by cancer cells in confluent cultures, which is apparently a manifestation of the general phenomenon of multicellular resistance. The aim of this study was to evaluate whether the anticancer effect of the recombinant protein TRAIL in vivo can be improved by the suppression of multicellular TRAIL-resistance using sorafenib and a tumor-penetrating peptide iRGD, c(CRGDKGPDC). The results testified a great increase in the resistance of human fibrosarcoma HT-1080 cells to izTRAIL both in confluent cultures and in spheroids. Sorafenib administered at nontoxic concentration effectively suppressed confluent- or spheroid-mediated TRAIL-resistance of HT-1080 cells in vitro. Sorafenib combined with iRGD significantly improved the anticancer effect of the recombinant protein izTRAIL in HT-1080 human fibrosarcoma grafts in BALB/c nude mice. Consistent with this finding, multicellular TRAIL-resistance may be a reason of inefficacy of izTRAIL alone in vivo. The anticancer effect of the recombinant protein izTRAIL in vivo may be improved in combination with sorafenib, an inhibitor of multicellular TRAIL resistance and iRGD, the tumor-penetrating peptide.
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spelling pubmed-63874602019-02-27 Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD Fadeev, Roman Chekanov, Alexey Solovieva, Marina Bezborodova, Olga Nemtsova, Elena Dolgikh, Nadezda Fadeeva, Irina Senotov, Anatoly Kobyakova, Margarita Evstratova, Yana Yakubovskaya, Raisa Akatov, Vladimir Int J Mol Sci Article One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is to provide effective penetration of drug molecules to cancer cells. TRAIL (TNFα-related apoptosis inducing ligand)/Apo2L is a highly selective anticancer agent. However, the recombinant TRAIL protein having high efficiency against cancer cells in vitro was not effective in clinical trials. Recently we have discovered an acquisition of TRAIL resistance by cancer cells in confluent cultures, which is apparently a manifestation of the general phenomenon of multicellular resistance. The aim of this study was to evaluate whether the anticancer effect of the recombinant protein TRAIL in vivo can be improved by the suppression of multicellular TRAIL-resistance using sorafenib and a tumor-penetrating peptide iRGD, c(CRGDKGPDC). The results testified a great increase in the resistance of human fibrosarcoma HT-1080 cells to izTRAIL both in confluent cultures and in spheroids. Sorafenib administered at nontoxic concentration effectively suppressed confluent- or spheroid-mediated TRAIL-resistance of HT-1080 cells in vitro. Sorafenib combined with iRGD significantly improved the anticancer effect of the recombinant protein izTRAIL in HT-1080 human fibrosarcoma grafts in BALB/c nude mice. Consistent with this finding, multicellular TRAIL-resistance may be a reason of inefficacy of izTRAIL alone in vivo. The anticancer effect of the recombinant protein izTRAIL in vivo may be improved in combination with sorafenib, an inhibitor of multicellular TRAIL resistance and iRGD, the tumor-penetrating peptide. MDPI 2019-01-27 /pmc/articles/PMC6387460/ /pubmed/30691192 http://dx.doi.org/10.3390/ijms20030525 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fadeev, Roman
Chekanov, Alexey
Solovieva, Marina
Bezborodova, Olga
Nemtsova, Elena
Dolgikh, Nadezda
Fadeeva, Irina
Senotov, Anatoly
Kobyakova, Margarita
Evstratova, Yana
Yakubovskaya, Raisa
Akatov, Vladimir
Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
title Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
title_full Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
title_fullStr Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
title_full_unstemmed Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
title_short Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
title_sort improved anticancer effect of recombinant protein iztrail combined with sorafenib and peptide irgd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387460/
https://www.ncbi.nlm.nih.gov/pubmed/30691192
http://dx.doi.org/10.3390/ijms20030525
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