title: Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists.
abstract: The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.
authors.affiliation: Departments of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. Doris-Benbrook@ouhsc.edu
authors.forename: Doris M
authors.initials: DM
authors.lastname: Benbrook
authors.forename: Scott A
authors.initials: SA
authors.lastname: Kamelle
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Guruswamy
authors.forename: Stan A
authors.initials: SA
authors.lastname: Lightfoot
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Rutledge
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Gould
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Hannafon
authors.forename: S Terence
authors.initials: ST
authors.lastname: Dunn
authors.forename: K Darrell
authors.initials: KD
authors.lastname: Berlin
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D023422:Skin Irritancy Tests; D013871:Thiones / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C508274:(((4-(ethoxycarbonyl)phenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methan-1-one; C508275:(((4-(ethoxycarbonyl)phenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione; C476105:(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione; D000970:Antineoplastic Agents; D002839:Chromans; D010671:Phenylurea Compounds; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013871:Thiones; D012313:RNA; D000410:Alanine Transaminase; D013890:Thiourea