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: Florian Rothweiler, Martin Michaelis, Peter Brauer, Jürgen Otte, Kristoffer Weber, Boris Fehse, Hans Wilhelm Doerr, Michael Wiese, Jörg Kreuter, Yousef Al-Abed, Ferdinando Nicoletti, Jindrich Cinatl Jr
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 12 Issue 12 Pg. 1023-30 (Dec 2010) ISSN: 1476-5586 [Electronic] United States
• PMID: 21170266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Multidrug Resistance-Associated Proteins
• saquinavir-NO
• Saquinavir
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Flow Cytometry
• Genes, p53
• Humans
• Mice
• Multidrug Resistance-Associated Proteins (metabolism)
• Saquinavir (analogs & derivatives, pharmacology)