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Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition
BACKGROUND: To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236185/ https://www.ncbi.nlm.nih.gov/pubmed/22174819 http://dx.doi.org/10.1371/journal.pone.0028487 |
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author | Guo, Wei Wu, Shuhong Wang, Li Wei, Xiaoli Liu, Xiaoying Wang, Ji Lu, Zhimin Hollingshead, Melinda Fang, Bingliang |
author_facet | Guo, Wei Wu, Shuhong Wang, Li Wei, Xiaoli Liu, Xiaoying Wang, Ji Lu, Zhimin Hollingshead, Melinda Fang, Bingliang |
author_sort | Guo, Wei |
collection | PubMed |
description | BACKGROUND: To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1. METHODOLOGY AND PRINCIPAL FINDINGS: In vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was ≤10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity. CONCLUSIONS: NSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors. |
format | Online Article Text |
id | pubmed-3236185 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32361852011-12-15 Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition Guo, Wei Wu, Shuhong Wang, Li Wei, Xiaoli Liu, Xiaoying Wang, Ji Lu, Zhimin Hollingshead, Melinda Fang, Bingliang PLoS One Research Article BACKGROUND: To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1. METHODOLOGY AND PRINCIPAL FINDINGS: In vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was ≤10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity. CONCLUSIONS: NSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors. Public Library of Science 2011-12-12 /pmc/articles/PMC3236185/ /pubmed/22174819 http://dx.doi.org/10.1371/journal.pone.0028487 Text en Guo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Guo, Wei Wu, Shuhong Wang, Li Wei, Xiaoli Liu, Xiaoying Wang, Ji Lu, Zhimin Hollingshead, Melinda Fang, Bingliang Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition |
title | Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition |
title_full | Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition |
title_fullStr | Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition |
title_full_unstemmed | Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition |
title_short | Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition |
title_sort | antitumor activity of a novel oncrasin analogue is mediated by jnk activation and stat3 inhibition |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236185/ https://www.ncbi.nlm.nih.gov/pubmed/22174819 http://dx.doi.org/10.1371/journal.pone.0028487 |
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