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: Doris M Benbrook, Scott A Kamelle, Suresh B Guruswamy, Stan A Lightfoot, Teresa L Rutledge, Natalie S Gould, Bethany N Hannafon, S Terence Dunn, K Darrell Berlin
• Journal: Investigational new drugs (Invest New Drugs) Vol. 23 Issue 5 Pg. 417-28 (Oct 2005) ISSN: 0167-6997 [Print] United States
• PMID: 16133793 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• (((4-(ethoxycarbonyl)phenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methan-1-one
• (((4-(ethoxycarbonyl)phenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione
• (((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione
• Antineoplastic Agents
• Chromans
• Phenylurea Compounds
• Receptors, Retinoic Acid
• Retinoid X Receptors
• Thiones
• RNA
• Alanine Transaminase
• Thiourea

Topics

• Alanine Transaminase (blood)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromans (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Inbred Strains
• Ovarian Neoplasms (drug therapy)
• Phenylurea Compounds (pharmacology)
• RNA (metabolism)
• Receptors, Retinoic Acid (agonists, genetics, metabolism)
• Retinoid X Receptors (agonists, genetics, metabolism)
• Skin Irritancy Tests
• Thiones (pharmacology)
• Thiourea (analogs & derivatives, pharmacology)
• Uterine Cervical Neoplasms (drug therapy, genetics, metabolism)
• Xenograft Model Antitumor Assays