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

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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 RARγ-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.

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Authors and Affiliations

  1. Departments of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73190

    Doris M. Benbrook, Scott A. Kamelle, Suresh B. Guruswamy, Teresa L. Rutledge, Natalie S. Gould & Bethany N. Hannafon

  2. Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73190

    Doris M. Benbrook & Suresh B. Guruswamy

  3. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73190

    Stan A. Lightfoot & S. Terence Dunn

  4. Department of Chemistry, Oklahoma State University, Stillwater, OK

    K. Darrell Berlin

  5. Department of OB/GYN, University of Oklahoma HSC, 920 Stanton L. Young Blvd., Room WP 2470, Oklahoma City, OK, 73104, USA

    Doris M. Benbrook

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  1. Doris M. Benbrook
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  2. Scott A. Kamelle
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Correspondence to Doris M. Benbrook.

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Benbrook, D.M., Kamelle, S.A., Guruswamy, S.B. et al. Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists. Invest New Drugs 23, 417–428 (2005). https://doi.org/10.1007/s10637-005-2901-5

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  • DOI: https://doi.org/10.1007/s10637-005-2901-5

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