title: The selectivity of austocystin D arises from cell-line-specific drug activation by cytochrome P450 enzymes.
abstract: The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D's selective cytotoxic activity. Here we show that the selective cytotoxic action of austocystin D arises from its selective activation by cytochrome P450 (CYP) enzymes in specific cancer cell lines, leading to induction of DNA damage in cells and in vitro. The potency and selectivity of austocystin D is lost upon inhibition of CYP activation and does not require MDR1 expression or activity. Furthermore, the pattern of cytotoxicity of austocystin D was distinct from doxorubicin and etoposide and unlike aflatoxin B(1), a compound that resembles austocystin D and is also activated by CYP enzymes to induce DNA damage. Theses results suggest that austocystin D may be of clinical benefit for targeting or overcoming chemoresistance.
authors.affiliation: Makoto Life Sciences, Inc., 15 DeAngelo Drive, Bedford, Massachusetts 01730, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Marks
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Park
authors.forename: Alexander
authors.initials: A
authors.lastname: Arefolov
authors.forename: Katie
authors.initials: K
authors.lastname: Russo
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishihara
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ring
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Clarke
authors.forename: Henry E
authors.initials: HE
authors.lastname: Pelish
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D016604:Aflatoxin B1 / Q000494:pharmacology*; D000348:Aflatoxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001230:Aspergillus / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000348:Aflatoxins; D000970:Antineoplastic Agents; C558970:austocystin D; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1