Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells
To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4′ dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic ac...
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creator | Bernard, Dannie Gebbia, Marinella Prabha, Swayam Gronda, Marcela MacLean, Neil Wang, Xiaoming Hurren, Rose Sukhai, Mahadeo A. Cho, Eunice E. Manolson, Morris F. Datti, Alessandro Wrana, Jeffrey Minden, Mark D. Al-Awar, Rima Aman, Ahmed Nislow, Corey Giaever, Guri Schimmer, Aaron D. |
description | To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4′ dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic activity. To determine the anti-leukemic mechanism of action of Deox B 7,4, we conducted a genome-wide screen in
Saccharomyces cerevisiae
and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function. |
doi_str_mv | 10.1007/s10495-015-1123-3 |
format | Article |
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Saccharomyces cerevisiae
and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function.</description><identifier>ISSN: 1360-8185</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-015-1123-3</identifier><identifier>PMID: 25832785</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Acidification ; Acidity ; Animals ; Antineoplastic Agents - pharmacology ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell Biology ; Cell Line, Tumor ; Chromones - pharmacology ; Guaiacol - analogs & derivatives ; Guaiacol - pharmacology ; Humans ; Inhibitors ; Leukemia ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Lysosomes - chemistry ; Lysosomes - drug effects ; Lysosomes - metabolism ; Mice ; Oncology ; Original Paper ; Saccharomyces cerevisiae ; Tubulin Modulators - pharmacology ; Vacuolar Proton-Translocating ATPases - metabolism ; Virology</subject><ispartof>Apoptosis (London), 2015-07, Vol.20 (7), p.948-959</ispartof><rights>Springer Science+Business Media New York 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-a13c0cc431bb6faacb1966792cb1eddf16a7cd49c7cb03e16a941ba3b085af243</citedby><cites>FETCH-LOGICAL-c372t-a13c0cc431bb6faacb1966792cb1eddf16a7cd49c7cb03e16a941ba3b085af243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-015-1123-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-015-1123-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27902,27903,41466,42535,51296</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25832785$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bernard, Dannie</creatorcontrib><creatorcontrib>Gebbia, Marinella</creatorcontrib><creatorcontrib>Prabha, Swayam</creatorcontrib><creatorcontrib>Gronda, Marcela</creatorcontrib><creatorcontrib>MacLean, Neil</creatorcontrib><creatorcontrib>Wang, Xiaoming</creatorcontrib><creatorcontrib>Hurren, Rose</creatorcontrib><creatorcontrib>Sukhai, Mahadeo A.</creatorcontrib><creatorcontrib>Cho, Eunice E.</creatorcontrib><creatorcontrib>Manolson, Morris F.</creatorcontrib><creatorcontrib>Datti, Alessandro</creatorcontrib><creatorcontrib>Wrana, Jeffrey</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Al-Awar, Rima</creatorcontrib><creatorcontrib>Aman, Ahmed</creatorcontrib><creatorcontrib>Nislow, Corey</creatorcontrib><creatorcontrib>Giaever, Guri</creatorcontrib><creatorcontrib>Schimmer, Aaron D.</creatorcontrib><title>Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4′ dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic activity. To determine the anti-leukemic mechanism of action of Deox B 7,4, we conducted a genome-wide screen in
Saccharomyces cerevisiae
and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function.</description><subject>Acidification</subject><subject>Acidity</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Chromones - pharmacology</subject><subject>Guaiacol - analogs & derivatives</subject><subject>Guaiacol - pharmacology</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Lysosomes - chemistry</subject><subject>Lysosomes - drug effects</subject><subject>Lysosomes - metabolism</subject><subject>Mice</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Saccharomyces cerevisiae</subject><subject>Tubulin Modulators - 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Academic</collection><jtitle>Apoptosis (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bernard, Dannie</au><au>Gebbia, Marinella</au><au>Prabha, Swayam</au><au>Gronda, Marcela</au><au>MacLean, Neil</au><au>Wang, Xiaoming</au><au>Hurren, Rose</au><au>Sukhai, Mahadeo A.</au><au>Cho, Eunice E.</au><au>Manolson, Morris F.</au><au>Datti, Alessandro</au><au>Wrana, Jeffrey</au><au>Minden, Mark D.</au><au>Al-Awar, Rima</au><au>Aman, Ahmed</au><au>Nislow, Corey</au><au>Giaever, Guri</au><au>Schimmer, Aaron D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells</atitle><jtitle>Apoptosis (London)</jtitle><stitle>Apoptosis</stitle><addtitle>Apoptosis</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>20</volume><issue>7</issue><spage>948</spage><epage>959</epage><pages>948-959</pages><issn>1360-8185</issn><eissn>1573-675X</eissn><abstract>To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4′ dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic activity. To determine the anti-leukemic mechanism of action of Deox B 7,4, we conducted a genome-wide screen in
Saccharomyces cerevisiae
and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>25832785</pmid><doi>10.1007/s10495-015-1123-3</doi><tpages>12</tpages></addata></record> |
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subjects | Acidification Acidity Animals Antineoplastic Agents - pharmacology Biochemistry Biomedical and Life Sciences Biomedicine Cancer Research Cell Biology Cell Line, Tumor Chromones - pharmacology Guaiacol - analogs & derivatives Guaiacol - pharmacology Humans Inhibitors Leukemia Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Lysosomes - chemistry Lysosomes - drug effects Lysosomes - metabolism Mice Oncology Original Paper Saccharomyces cerevisiae Tubulin Modulators - pharmacology Vacuolar Proton-Translocating ATPases - metabolism Virology |
title | Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells |
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