title: Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells.
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.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Rm 9-516, 610 University Ave, Toronto, ON, M5G 2M9, Canada.
authors.forename: Dannie
authors.initials: D
authors.lastname: Bernard
authors.forename: Marinella
authors.initials: M
authors.lastname: Gebbia
authors.forename: Swayam
authors.initials: S
authors.lastname: Prabha
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Neil
authors.initials: N
authors.lastname: MacLean
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Mahadeo A
authors.initials: MA
authors.lastname: Sukhai
authors.forename: Eunice E
authors.initials: EE
authors.lastname: Cho
authors.forename: Morris F
authors.initials: MF
authors.lastname: Manolson
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wrana
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aman
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D012441:Saccharomyces cerevisiae; D050257:Tubulin Modulators / Q000494:pharmacology*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D050257:Tubulin Modulators; C000603980:deoxysappanone B 7,4' dimethyl ether; D006139:Guaiacol; D025262:Vacuolar Proton-Translocating ATPases