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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Veröffentlicht in:Apoptosis (London) 2015-07, Vol.20 (7), p.948-959
Hauptverfasser: 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.
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container_end_page 959
container_issue 7
container_start_page 948
container_title Apoptosis (London)
container_volume 20
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.
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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. 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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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