Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases

Njar, Vincent C.O.; Gediya, Lalji K.; Purushottamachar, Puranik; Chopra, Pankaj; Vasaitis, Tadas S.; Khandelwal, Aakanksha; Mehta, Jhalak; Huynh, Carlic; Belosay, Aashvini; Patel, Jyoti

doi:10.1016/j.bmc.2006.02.041

Cited by 129 publications

(105 citation statements)

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“…Our RAMBAs are also considered to be atypical, because in addition to being potent inhibitors of ATRA metabolism (able to enhance the antiproliferative action of ATRA), they also possess intrinsic potent cancer antiproliferative activities (Njar et al, 2000(Njar et al, , 2006aNjar, 2002;Patel et al, 2004;Huynh et al, 2006;Belosay et al, 2006). We have also found that our RAMBAs appear to have different potencies in different types of human cancer cell lines.…”

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confidence: 75%

“…Whereas several categories of nonretinoidal RAMBAs have been reported (reviewed in Njar, 2002;Njar et al, 2006a), only a few retinoidal RAMBAs developed by our group are known. Our RAMBAs are also considered to be atypical, because in addition to being potent inhibitors of ATRA metabolism (able to enhance the antiproliferative action of ATRA), they also possess intrinsic potent cancer antiproliferative activities (Njar et al, 2000(Njar et al, , 2006aNjar, 2002;Patel et al, 2004;Huynh et al, 2006;Belosay et al, 2006).…”

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confidence: 99%

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Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

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Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER þ ve, MCF-7 and T-47D) and oestrogen receptor negative (ER Àve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumuor xenografts. The ER þ ve cell lines were more sensitive (IC 50 values between 3.0 and 609 nM) to the RAMBAs than the ER Àve MDA-MB-231 cell line (IC 50 ¼ 5.6 -24.0 mM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-a (ER-a). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (480%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, Po0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (Po0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer.

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confidence: 75%

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Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

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“…In the target cells, retinol undergoes bio-activation to form retinal, retinoic acids (RAs), or hydroxyretroretinol [1]. Alcohol dehydrogenase/reductases (ADHs) are the key enzymes responsible for inter-conversion between retinol and retinal.…”

Section: Introductionmentioning

confidence: 99%

“…CYP2C9 contributes about 5 to 10 % to the total 4-hydroxylation of all-trans-RA. CYP26, which expresses in very low levels in a number of tissues including cell lines, also plays a role in the process [1,3].…”

Section: Introductionmentioning

confidence: 99%

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

Wang

Chen

Xie

et al. 2008

Biochemical Pharmacology

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A panel of retinoids and carotenoids was screened as potential inducers of CYP3A4 through the RXR/VDR-mediated signaling pathway. Transient transfection assays revealed that 3 out of 12 retinoids screened transactivated RXRα/VDR and induced CYP3A4 reporter activity. These three retinoids are the active metabolites of retinoids, 9-cis-retinal, 9-cis-retinoic acid (9-cis-RA), and alltrans-retinoic acid (all-trans-RA). 9-cis-RA and all-trans-RA, preferentially transactivated the RXR/ VDR heterodimers and RXR homodimers. Retinoids and VDR agonist 1α, 25-dihydroxyvitamin D 3 , but not PXR or CAR activator, could induce Cyp3a11 mRNA level in hepatocytes derived from PXR/CAR double null mouse. Moreover, retinoids induced CYP3A4 enzyme activity in HepG2 human hepatoma and Caco-2 human colorectal adenocarcinoma cells. A direct role of retinoidmediated CYP3A4 induction through RXRα/VDR was proved by the results that 9-cis-retinal, 9-cis-RA, and all-trans-RA recruited RXRα and VDR to CYP3A4 regulatory region pER6 (proximal everted repeat with a 6-nucleotide spacer) and dXREM (distal xenobiotic-responsive enhancer module). Thus, using various approaches, we have unequivocally demonstrated that retinoids transactivate RXR/VDR heterodimers and RXR homodimers and induce CYP3A expression at mRNA as well as enzyme activity levels in both liver and intestinal cells. It is possible that retinoids might alter endobiotic metabolism through CYP3A4 induction in vivo.

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“…All-trans retinoic acid undergoes cytochrome P450 metabolism to form inactive polar metabolites (Njar et al, 2006b). The metabolism of ATRA by CYP enzymes (particularly by CYP26) and dysregulation of gene expression contribute to the cancerous phenotype.…”

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confidence: 99%

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

2008

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Combining drugs, which target different signalling pathways, often decreases adverse side effects while increasing the efficacy of treatment. The objective of our study was to determine if the combination of our novel atypical retinoic acid metabolism-blocking agent (RAMBA) VN/66-1 and a promising histone deacetylase inhibitor N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide (MS-275) would show enhanced antineoplastic activity on human PC-3 prostate cancer cells/ tumours and also to decipher the molecular mechanisms of action. The combination of VN/66-1 þ MS-275 was found to be synergistic in inhibiting PC-3 cell growth, caused cell cytostaticity/cytotoxicity and induced marked G2/M phase arrest and apoptosis. In mice with well-established PC-3 tumours, VN/66-1 (5 and 10 mg kg À1 day À1 ) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg À1 day À1 ) þ MS-275 (2.5 mg kg À1 day À1 ) for 18 days resulted in an 85% reduction in final mean tumour volume compared with control and was more effective than either agent alone. Mechanistic studies indicated that treatment of PC-3 cells/tumours with VN/66-1 þ MS-275 caused DNA damage (upregulation of gH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-b, p21 WAF1/CIP1 , E-cadherin, and Bad and downregulation of Bcl-2. These data suggest that the mechanism of action of the combination of agents is DNA damage-induced p21 activation, resulting in inhibition of the Cdc2/cyclin B complex and accumulation of cells in G2/M phase. In addition, the combination caused modulation and induction of apoptosis. These results suggest that VN/66-1 or its combination with MS-275 may be a novel therapy for the treatment of prostate carcinoma.

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Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases

Cited by 129 publications

References 91 publications

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

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