Sodium salicylate acts through direct inhibition of phosphoinositide 3-kinase-like kinases to modulate topoisomerase-mediated DNA damage responses

Chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs) exhibit diverse pharmacological and biological activities mainly through their inhibitory effect on cyclooxygenase (COX). However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic e...

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Veröffentlicht in:European journal of pharmacology 2010-07, Vol.638 (1), p.13-20
Hauptverfasser: Fan, Jia-Rong, Huang, Ting-Hsiang, Wen, Chen-Yu, Shen, Tang-Long, Li, Tsai-Kun
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Huang, Ting-Hsiang
Wen, Chen-Yu
Shen, Tang-Long
Li, Tsai-Kun
description Chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs) exhibit diverse pharmacological and biological activities mainly through their inhibitory effect on cyclooxygenase (COX). However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic effects of NSAIDs. Here, we explored the potential relationship between chemopreventive NSAIDs and DNA damage responses induced by treatment with topoisomerase-targeting drugs. (1) Sodium salicylate, a non-COX-selective NSAID, was shown to reduce DNA damage-induced RPA and p53 phosphorylation. (2) The formation of enzyme cleavable complexes by topoisomerase-targeting drugs was not affected in the presence of sodium salicylate. (3) The attenuating effect of NSAIDs on the DNA damage responses is COX-2-independent, since COX-2-selective inhibitors failed to inhibit DNA damage-induced phosphorylation of replication protein A (RPA) and p53. (4) This COX-2-independent attenuating effect was mediated through interference of neither nuclear factor kappa B nor extracellular signal-regulated kinase pathways. (5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. Together, our study provides evidence that NSAIDs exhibit a novel COX-independent modulating activity of NSAIDs on the DNA damage responses and it is through inhibition of phosphoinositide 3-kinase-like kinases.
doi_str_mv 10.1016/j.ejphar.2010.04.012
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(5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. 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However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic effects of NSAIDs. Here, we explored the potential relationship between chemopreventive NSAIDs and DNA damage responses induced by treatment with topoisomerase-targeting drugs. (1) Sodium salicylate, a non-COX-selective NSAID, was shown to reduce DNA damage-induced RPA and p53 phosphorylation. (2) The formation of enzyme cleavable complexes by topoisomerase-targeting drugs was not affected in the presence of sodium salicylate. (3) The attenuating effect of NSAIDs on the DNA damage responses is COX-2-independent, since COX-2-selective inhibitors failed to inhibit DNA damage-induced phosphorylation of replication protein A (RPA) and p53. (4) This COX-2-independent attenuating effect was mediated through interference of neither nuclear factor kappa B nor extracellular signal-regulated kinase pathways. (5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. 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Drug treatments</subject><subject>Phosphoinositide 3-kinase-like kinase</subject><subject>Phosphorylation - drug effects</subject><subject>Protein-Serine-Threonine Kinases - antagonists &amp; inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Replication Protein A - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Sodium salicylate</subject><subject>Sodium Salicylate - pharmacology</subject><subject>Topoisomerase cleavable complex</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - antagonists &amp; inhibitors</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1TAUhC1ERW8Lb4CQN4hVLv7LjzdIVaGAVLWLwtpy7OPGt0kc7ASpr8ET45AL7GBh2Rp9M7bPIPSSkj0ltHp72MNh6nTcM5IlIvaEsidoR5taFqSm7CnaEUJFwaSUp-gspQMhpJSsfIZOGRGkqjjZoR93wfplwEn33jz2egaszZzw3MWw3HfY-ghmxn7sfOtnH0YcHJ66kPLyY0hZs4B58eBHnaDo_QPg7ZwzAh6CXX6FzmEKPoUB4ooNYH1WLX5_c4GtHvQ94AhpCmP2PUcnTvcJXhz3c_T16sOXy0_F9e3Hz5cX14URjM-FFI62xkkQVhpbQWN4XQJtgUnnDKtcJWhLdGtaVjf52841BnTLK0oElVzyc_Rmy51i-LZAmtXgk4G-1yOEJSlJhGjqsir_S9ac06Ys6zVTbKSJIaUITk3RDzo-KkrUWps6qK02tdamiFC5tmx7dbxgafNs_ph-95SB10dAJ6N7F_VofPrLsaZinK9B7zYO8uC-e4gqGQ-jga1HZYP_90t-Arfju3Q</recordid><startdate>20100725</startdate><enddate>20100725</enddate><creator>Fan, Jia-Rong</creator><creator>Huang, Ting-Hsiang</creator><creator>Wen, Chen-Yu</creator><creator>Shen, Tang-Long</creator><creator>Li, Tsai-Kun</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope></search><sort><creationdate>20100725</creationdate><title>Sodium salicylate acts through direct inhibition of phosphoinositide 3-kinase-like kinases to modulate topoisomerase-mediated DNA damage responses</title><author>Fan, Jia-Rong ; Huang, Ting-Hsiang ; Wen, Chen-Yu ; Shen, Tang-Long ; Li, Tsai-Kun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-94f1bcf9e4d9cd6e8c375e1be29ffc26f641b0abcb278925ff8ceab3610419393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Biological and medical sciences</topic><topic>Camptothecin - pharmacology</topic><topic>Cell Cycle Proteins - antagonists &amp; inhibitors</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Death - drug effects</topic><topic>Cyclooxygenase</topic><topic>Cyclooxygenase 2 Inhibitors - pharmacology</topic><topic>DNA Damage - drug effects</topic><topic>DNA damage response</topic><topic>DNA Topoisomerases - drug effects</topic><topic>DNA-Activated Protein Kinase - antagonists &amp; inhibitors</topic><topic>DNA-Activated Protein Kinase - metabolism</topic><topic>DNA-Binding Proteins - antagonists &amp; inhibitors</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Interactions</topic><topic>HCT116 Cells</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>NF-kappa B</topic><topic>Nuclear factor kappa B</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphoinositide 3-kinase-like kinase</topic><topic>Phosphorylation - drug effects</topic><topic>Protein-Serine-Threonine Kinases - antagonists &amp; inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Replication Protein A - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Sodium salicylate</topic><topic>Sodium Salicylate - pharmacology</topic><topic>Topoisomerase cleavable complex</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - antagonists &amp; inhibitors</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fan, Jia-Rong</creatorcontrib><creatorcontrib>Huang, Ting-Hsiang</creatorcontrib><creatorcontrib>Wen, Chen-Yu</creatorcontrib><creatorcontrib>Shen, Tang-Long</creatorcontrib><creatorcontrib>Li, Tsai-Kun</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fan, Jia-Rong</au><au>Huang, Ting-Hsiang</au><au>Wen, Chen-Yu</au><au>Shen, Tang-Long</au><au>Li, Tsai-Kun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sodium salicylate acts through direct inhibition of phosphoinositide 3-kinase-like kinases to modulate topoisomerase-mediated DNA damage responses</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2010-07-25</date><risdate>2010</risdate><volume>638</volume><issue>1</issue><spage>13</spage><epage>20</epage><pages>13-20</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>Chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs) exhibit diverse pharmacological and biological activities mainly through their inhibitory effect on cyclooxygenase (COX). However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic effects of NSAIDs. Here, we explored the potential relationship between chemopreventive NSAIDs and DNA damage responses induced by treatment with topoisomerase-targeting drugs. (1) Sodium salicylate, a non-COX-selective NSAID, was shown to reduce DNA damage-induced RPA and p53 phosphorylation. (2) The formation of enzyme cleavable complexes by topoisomerase-targeting drugs was not affected in the presence of sodium salicylate. (3) The attenuating effect of NSAIDs on the DNA damage responses is COX-2-independent, since COX-2-selective inhibitors failed to inhibit DNA damage-induced phosphorylation of replication protein A (RPA) and p53. (4) This COX-2-independent attenuating effect was mediated through interference of neither nuclear factor kappa B nor extracellular signal-regulated kinase pathways. (5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. Together, our study provides evidence that NSAIDs exhibit a novel COX-independent modulating activity of NSAIDs on the DNA damage responses and it is through inhibition of phosphoinositide 3-kinase-like kinases.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>20406630</pmid><doi>10.1016/j.ejphar.2010.04.012</doi><tpages>8</tpages></addata></record>
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subjects Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Ataxia Telangiectasia Mutated Proteins
Biological and medical sciences
Camptothecin - pharmacology
Cell Cycle Proteins - antagonists & inhibitors
Cell Cycle Proteins - metabolism
Cell Death - drug effects
Cyclooxygenase
Cyclooxygenase 2 Inhibitors - pharmacology
DNA Damage - drug effects
DNA damage response
DNA Topoisomerases - drug effects
DNA-Activated Protein Kinase - antagonists & inhibitors
DNA-Activated Protein Kinase - metabolism
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - metabolism
Drug Interactions
HCT116 Cells
Humans
Medical sciences
NF-kappa B
Nuclear factor kappa B
Pharmacology. Drug treatments
Phosphoinositide 3-kinase-like kinase
Phosphorylation - drug effects
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - metabolism
Replication Protein A - metabolism
Signal Transduction - drug effects
Sodium salicylate
Sodium Salicylate - pharmacology
Topoisomerase cleavable complex
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - antagonists & inhibitors
Tumor Suppressor Proteins - metabolism
title Sodium salicylate acts through direct inhibition of phosphoinositide 3-kinase-like kinases to modulate topoisomerase-mediated DNA damage responses
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