title: Collateral sensitivity of multidrug-resistant cells to the orphan drug tiopronin.
abstract: A major challenge in the treatment of cancer is multidrug resistance (MDR) that develops during chemotherapy. Here we demonstrate that tiopronin (1), a thiol-substituted N-propanoylglycine derivative, was selectively toxic to a series of cell lines expressing the drug efflux pump P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1). Treatment of MDR cells with 1 led to instability of the ABCB1 mRNA and consequently a reduction in P-gp protein, despite functional assays demonstrating that tiopronin does not interact with P-gp. Long-term exposure of P-gp-expressing cells to 1 sensitized them to doxorubicin and paclitaxel, both P-gp substrates. Treatment of MRP1-overexpressing cells with tiopronin led to a significant reduction in MRP1 protein. Synthesis and screening of analogues of tiopronin demonstrated that the thiol functional group was essential for collateral sensitivity while substitution of the amino acid backbone altered but did not destroy specificity, pointing to future development of targeted analogues.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Goldsborough
authors.forename: Misty D
authors.initials: MD
authors.lastname: Handley
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Dulcey
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Pluchino
authors.forename: Pavitra
authors.initials: P
authors.lastname: Kannan
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.forename: Gary
authors.initials: G
authors.lastname: Griffiths
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009965:Orphan Drug Production; D017239:Paclitaxel / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D008625:Tiopronin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D012333:RNA, Messenger; D008625:Tiopronin; C513055:ABCB1 protein, human; C421109:multidrug resistance-associated protein 1