title: The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function.
abstract: Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.
authors.affiliation: Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Lilly
authors.initials: L
authors.lastname: Chai
authors.forename: Rajashree P
authors.initials: RP
authors.lastname: McLaren
authors.forename: Ann
authors.initials: A
authors.lastname: Byrne
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Chuang
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Huang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Dufault
authors.forename: Joshua
authors.initials: J
authors.lastname: Pacheco
authors.forename: Shruti
authors.initials: S
authors.lastname: Madhiwalla
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Zhang
authors.forename: Mindy
authors.initials: M
authors.lastname: Zhang
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
authors.forename: Kara
authors.initials: K
authors.lastname: Carter
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xiang
authors.forename: Michael
authors.initials: M
authors.lastname: Vasconcelles
authors.forename: Mark A
authors.initials: MA
authors.lastname: Goldberg
authors.forename: Diane P
authors.initials: DP
authors.lastname: Copeland
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Klinger
authors.forename: James
authors.initials: J
authors.lastname: Lillie
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Madden
authors.forename: Yide A
authors.initials: YA
authors.lastname: Jiang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C520404:(2-(2',3'-dihydrobenzo(1,4)dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethylethyl)nonanoic acid amide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004146:Dioxanes; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D004317:Doxorubicin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase