Synthesis, Structure-Activity Relationships, and RARγ-Ligand Interactions of Nitrogen Heteroarotinoids.

Dhar, Arindam; Liu, Shengquan; Klucik, Jozef; Berlin, K. Darrell; Madler, M. M.; Lu, Shuo; Ivey, R. Todd; Zacheis, D.; Brown, Chad W.; Nelson, E. C.; Birckbichler, Paul J.; Benbrook, Doris M.

doi:10.1021/jm990593s

Cited by 11 publications

(17 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The importance of RARγ activation in skin cancer was demonstrated by comparisons of Hets, which differed by single structural alterations that regulated their abilities to activate the RARγ receptor. A Het that activates all six nuclear receptors (NHet90) induced significantly greater growth inhibition of vulvar carcinoma cell lines in comparison to structurally related compounds, that activate all retinoid receptors except RARγ (NHet17 and NHet86) [16]. Interestingly, Hets containing three-atom urea or thiourea linkers, which increased the flexibility of their conformations, regulated growth and differentiation similar to RA, but did not activate the RARs and RXRs [18].…”

Section: Introductionmentioning

confidence: 97%

“…Individual structural alterations of Hets greatly affected their selectivities for individual RAR and RXRs (Figure 1) [12,[15][16][17]. A Het that activated RXRs only (OHet72) was found to be sufficient to inhibit establishment of head and neck xenograft tumors, while a retinoid that activated both RARs and RXRs (SHet50) exerted greater growth inhibitory activity [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…SHetA2 (see structure in Fig. 1A) is such a compound because it did not activate retinoic acid receptor and retinoid X receptor receptors in receptor cotransfection assays and reporter cell lines (4), rescue or induce embryonic malformations in a RALDH knockout mouse model (5), or cause skin irritancy in a murine topical irritancy model (6). Thus, SHetA2 functions independently of retinoid receptors (7,8).…”

Section: Introductionmentioning

confidence: 99%

CAAT/Enhancer Binding Protein Homologous Protein–Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells

et al. 2008

Self Cite

View full text Add to dashboard Cite

The flexible heteroarotinoids (Flex-Het) represent a novel type of atypical retinoids lacking activity in binding to and transactivating retinoid receptors. Preclinical studies have shown that Flex-Hets induce apoptosis of cancer cells while sparing normal cells and exhibit anticancer activity in vivo with improved therapeutic ratios over conventional retinoid receptor agonists. Flex-Hets have been shown to induce apoptosis through activation of the intrinsic apoptotic pathway. The present study has revealed a novel mechanism underlying Flex-Het-induced apoptosis involving induction of death receptor 5 (DR5). The representative Flex-Het SHetA2 effectively inhibited the growth of human lung cancer cells in cell culture and in mice. SHetA2 induced apoptosis, which could be abrogated by silencing caspase-8 expression, indicating that ShetA2 triggers a caspase-8-dependent apoptosis. Accordingly, SHetA2 up-regulated DR5 expression, including cell surface levels of DR5, and augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Importantly, small interfering RNA (siRNA)-mediated blockade of DR5 induction conferred cell resistance to SHetA2-induced apoptosis, as well as SHetA2/TRAIL-induced apoptosis. These results show that DR5 induction is a key component of apoptosis induced by SHetA2 or by SHetA2 combined with TRAIL. SHetA2 exerted CAAT/enhancerbinding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Consistently, SHetA2 induced CHOP expression, which paralleled DR5 up-regulation, whereas siRNA-mediated blockage of CHOP induction prevented DR5 up-regulation, indicating CHOP-dependent DR5 up-regulation by SHetA2. Collectively, we conclude that CHOP-dependent DR5 up-regulation is a key event mediating SHetA2-induced apoptosis. [Cancer Res 2008;68(13):5335-44]

show abstract

“…The synthetic retinoids (heteroarotinoids -gifts of K. Darrell Berlin, Oklahoma State University) were synthesized as previously described [30][31][32] . The 9-cis-RA (BIOMOL, Plymouth Meeting, PA), heteroarotinoids and PFTα (AG Scientific, San Diego GA) were dissolved in dimethyl sulfoxide (DMSO) as 1000× stock solutions, so that the final concentration of DMSO in all cultures was less than 0.1%, which is not cytotoxic and does not induce differentiation.…”

Section: Methodsmentioning

confidence: 99%

Retinoids Chemosensitize Ovarian Cancer Cell Lines to Cisplatin Independent of Nuclear Receptors and p53

Guruswamy¹,

Benbrook²

2006

American J. of Pharmacology and Toxicology

Self Cite

View full text Add to dashboard Cite

Treatment of ovarian cancer with cisplatin-based chemotherapy is highly toxic and is often followed by cancer recurrence. Repeated treatments with cisplatin frequently result in the development of resistance to this drug. Drugs with low toxicity that could enhance the tumor cell killing effects of cisplatin could potentially reduce the toxicity and enhance the efficacy of cisplatin. The mechanism of cell kill by cisplatin is partially due to induction of apoptosis through the p53 pathway. Retinoids can regulate apoptosis through nuclear retinoic acid receptors, but the role of p53 in the mechanism varies with the individual retinoid and cell type. The objective of this study was to evaluate the potential of receptor-active and -independent retinoids as chemosensitization of ovarian cancer cell lines with different p53 status. The growth of two ovarian cancer cell lines, OVCAR-3 that has wild type p53 and Caov-3 that has mutant type, was evaluated in the presence and absence of various combinations of cisplatin, a series of retinoids and a chemical inhibitor of p53 transactivation activity (pifithrinα). Both receptor active and receptor independent retinoids chemosensitized the two cell lines to cisplatin. PFTα partially attenuated growth inhibition by cisplatin, slightly enhanced the growth inhibition of retinoids and did not affect growth inhibition when retinoids were used in combination with cisplatin. RNase protection demonstrated that PFTα did not alter retinoid effects on p53 regulated genes. In conclusion, retinoids chemosensitize both sensitive and resistant ovarian cancer cells to cisplatin through mechanisms independent of nuclear retinoid receptors and p53.

show abstract

Synthesis, Structure-Activity Relationships, and RARγ-Ligand Interactions of Nitrogen Heteroarotinoids.

Cited by 11 publications

References 0 publications

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

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

CAAT/Enhancer Binding Protein Homologous Protein–Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells

Retinoids Chemosensitize Ovarian Cancer Cell Lines to Cisplatin Independent of Nuclear Receptors and p53

Contact Info

Product

Resources

About