Identification of cetrimonium bromide and irinotecan as compounds with synthetic lethality against NDRG1 deficient prostate cancer cells

• Published in: Cancer biology & therapy 2013-05, Vol.14 (5), p.401-410
• Main Authors: Wissing, Michel D, Mendonca, Janet, Kim, Eunice, Kim, Eugene, Shim, Joong S., Kaelber, Nadine S., Kant, Huub, Hammers, Hans, Commes, Therese, Van Diest, Paul J., Liu, Jun O., Kachhap, Sushant K.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cell Cycle Proteins - deficiency; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Growth Processes - drug effects; Cell Line, Tumor; cetrimonium bromide (CTAB); Cetrimonium Compounds - pharmacology; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; invasion; irinotecan; Male; Middle Aged; N-myc downstream regulated gene 1 (NDRG1); prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Research Paper; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Surface-Active Agents - pharmacology; synthetic lethality; topoisomerase I
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.23759

The N-myc downstream regulated gene 1 (NDRG1) has been identified as a metastasis-suppressor gene in prostate cancer (PCa). Compounds targeting PCa cells deficient in NDRG1 could potentially decrease invasion/metastasis of PCa. A cell based screening strategy was employed to identify small molecules that selectively target NDRG1 deficient PCa cells. DU-145 PCa cells rendered deficient in NDRG1 expression by a lentiviral shRNA-mediated knockdown strategy were used in the primary screen. Compounds filtered from the primary screen were further validated through proliferation and clonogenic survival assays in parental and NDRG1 knockdown PCa cells. Screening of 3360 compounds revealed irinotecan and cetrimonium bromide (CTAB) as compounds that exhibited synthetic lethality against NDRG1 deficient PCa cells. A three-dimensional (3-D) invasion assay was utilized to test the ability of CTAB to inhibit invasion of DU-145 cells. CTAB was found to remarkably decrease invasion of DU-145 cells in collagen matrix. Our results suggest that CTAB and irinotecan could be further explored for their potential clinical benefit in patients with NDRG1 deficient PCa.