title: Anticancer effects of the nitric oxide-modified saquinavir derivative saquinavir-NO against multidrug-resistant cancer cells.
abstract: The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Peter
authors.initials: P
authors.lastname: Brauer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Otte
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Weber
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.forename: Hans Wilhelm
authors.initials: HW
authors.lastname: Doerr
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D019258:Saquinavir / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019258:Saquinavir; C557004:saquinavir-NO; C421109:multidrug resistance-associated protein 1