Discovery of Novel Retinoic Acid Receptor Agonists Having Potent Antiproliferative Activity in Cervical Cancer Cells

Zhang, Lin; Nadzan, Alex M.; Heyman, Richard A.; D, Love; Mais, Dale E.; Croston, Glenn; Lamph, William W.; Boehm, Marcus F.

doi:10.1021/jm960285j

Cited by 31 publications

(14 citation statements)

References 20 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another approach to cure cancer is based on retinoids representing natural and synthetic derivatives of vitamin A, regulating cell growth (Nagpal et al 1996;Zhang et al 1996), apoptosis (Massaro and Massaro 2000), and homeostasis (Wan et al 2000). Apart from these effects, 13cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) have been found to promote differentiation of tumors into a more benign cell type.…”

Section: Introductionmentioning

confidence: 99%

Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

et al. 2005

View full text Add to dashboard Cite

Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX-) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 microM, 1 microM, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX- tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology.

show abstract

Section: Introductionmentioning

confidence: 99%

Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

et al. 2005

View full text Add to dashboard Cite

show abstract

“…(1) are characterized by conformational flexibility and the lack of subtypeselective functionalities on the linkers that can function as Hbond donors such as the native polyenes 1.1 and 1.2 and chalcones BMS181156 1.6 [21] and Ch55 1.7 [22]. The 3,5-di-tert-butylphenyl-based ALRT1550 (LGD1550) 1.5 [23] and analogues designed around meta-substituted aromatic ring linkers or the corresponding heteroaryl derivatives are also pan-agonists. Although conformationally constrained by the aryl rings, typical arotinoids such as TTNPB 1.3 [18] and TTAB 1.5 [24] bind also the three subtypes.…”

Section: Pan-rar Agonistsmentioning

confidence: 99%

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Maire¹,

Álvarez²,

Shankaranarayanan³

et al. 2012

CTMC

View full text Add to dashboard Cite

Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.

show abstract

“…12 Furthermore, it has been shown to be 300-fold more potent than all-transretinoic acid in inhibiting the proliferation of cervical carcinoma cells in vitro. 1 Retinoids have also demonstrated activity in preventing breast cancer in animal models. In a rat model, 9-cis-retinoic acid (an RAR and RXR panagonist) was more effective than all-trans-retinoic acid (an RAR-selective agonist) in preventing breast tumours.…”

Section: Retinoids In Cancermentioning

confidence: 99%

“…For example, they modulate cellular proliferation and differentiation, and regulate apoptosis. 1,2 Because of their involvement in many physiological pathways, retinoid drugs have clinical potential in several therapeutic areas.…”

mentioning

confidence: 99%

Novel retinoids with receptor selectivity and functional selectivity

Johnson

Chandraratna

1999

Br J Dermatol

View full text Add to dashboard Cite

Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.

show abstract

Discovery of Novel Retinoic Acid Receptor Agonists Having Potent Antiproliferative Activity in Cervical Cancer Cells

Cited by 31 publications

References 20 publications

Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Novel retinoids with receptor selectivity and functional selectivity

Contact Info

Product

Resources

About