title: ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin.
abstract: The realization, that the androgen receptor (AR) is essential for prostate cancer (PC) even after relapse following androgen deprivation therapy motivated the search for novel types of AR inhibitors. We proposed that targeting AR expression versus its function would work in cells having either wild type or mutant AR as well as be independent of androgen synthesis pathways. Previously, using a phenotypic screen in androgen-independent PC cells we identified a small molecule inhibitor of AR, ARTIK-52. Treatment with ARTIK-52 caused the loss of AR protein and death of AR-positive, but not AR-negative, PC cells. Here we present data that ARTIK-52 induces degradation of AR mRNA through a mechanism that we were unable to establish. However, we found that ARTIK-52 is toxic to breast cancer (BC) cells expressing AR, although they were not sensitive to AR knockdown, suggesting an AR-independent mechanism of toxicity. Using different approaches we detected that ARTIK-52 induces replication-dependent double strand DNA breaks exclusively in cancer cells of prostate and breast origin, while not causing DNA damage, or any toxicity, in normal cells, as well as in non-PC and non-BC tumor cells, independent of their proliferation status. This amazing specificity, combined with such a basic mechanism of toxicity, makes ARTIK-52 a potentially useful tool to discover novel attractive targets for the treatment of BC and PC. Thus, phenotypic screening allowed us to identify a compound, whose properties cannot be predicted based on existing knowledge and moreover, uncover a barely known link between AR and DNA damage response in PC and BC epithelial cells.
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Fleyshman
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Cheney
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Anda
authors.initials: A
authors.lastname: Ströse
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Shaila
authors.initials: S
authors.lastname: Mudambi
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Safina
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Mairead
authors.initials: M
authors.lastname: Commane
authors.affiliation: b Department of Chemistry , Cleveland BioLabs , Buffalo , NY , USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Purmal
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Morgan
authors.affiliation: c Collaborative Life Sciences Building (CLSB), Oregon Health & Science University , Portland , OR , USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: c Collaborative Life Sciences Building (CLSB), Oregon Health & Science University , Portland , OR , USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Gray
authors.affiliation: c Collaborative Life Sciences Building (CLSB), Oregon Health & Science University , Portland , OR , USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: d Department of Surgery , Otolaryngology and Yale Cancer Center, Yale University School of Medicine , New Haven , CT , USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.affiliation: a Department of Cell Stress Biology , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Gurova
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008856:Microscopy, Fluorescence; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C000612653:ARTIK-52; D059002:Androgen Receptor Antagonists; D002227:Carbazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: ARTIK-52; DNA damage; androgen receptor; breast cancer; p53; prostate cancer