Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

Invest New Drugs. 2005 Oct;23(5):417-28. doi: 10.1007/s10637-005-2901-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinoid X Receptors / agonists
  • Retinoid X Receptors / genetics
  • Retinoid X Receptors / metabolism
  • Skin Irritancy Tests
  • Thiones / pharmacology*
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Xenograft Model Antitumor Assays


  • (((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