A New Simple and High-Yield Synthesis of Suberoylanilide Hydroxamic Acid and Its Inhibitory Effect Alone or in Combination with Retinoids on Proliferation of Human Prostate Cancer Cells

Gediya, Lalji K.; Chopra, Pankaj; Purushottamachar, Puranik; Maheshwari, Neha; Njar, Vincent C.O.

doi:10.1021/jm058214k

Cited by 94 publications

(71 citation statements)

References 9 publications

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“…Drugs CDDO-Im, LG100268, and vorinostat were synthesized as previously described (21)(22)(23)(24), and LG101506 was synthesized by J-Star Research. Carboplatin and paclitaxel (C/P) were provided by the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis of the NCI.…”

Section: Methodsmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1b, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1);

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Section: Methodsmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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“…Our RAMBAs, however, based on the retinoid scaffold are considered 'atypical RAMBAs', because they are also endowed with multiple anticancer activities. On the basis of several studies in our lab, it is now evident that the anticancer activities of our RAMBAs cannot be explained by inhibition of ATRA metabolism alone (Patel et al, 2004(Patel et al, , 2007bGediya et al, 2005;Belosay et al, 2006;Huynh et al, 2006). We recently examined the growth inhibitory effects of one of our lead atypical RAMBAs VN/ 66-1 ( Figure 1A) in combination with clinically used suberoylanilide hydroxamic acid (SAHA, a HDACI) on the androgen receptor-positive human prostate LNCaP cell line (Gediya et al, 2005).…”

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confidence: 99%

“…Histone deacetylase inhibitors have been reported to have growth inhibitory activities in PCa models both in vitro and in vivo (Butler et al, 2000;Nakayama et al, 2001;Gediya et al, 2005). In addition, HDACIs when combined with retinoids (e.g., ATRA, 9-cis retinoic acid (9-CRA) or 13-cis-retinoic acid (13-CRA)) display enhanced (additive) anticancer activities (Pili et al, 2001;Gediya et al, 2005;Qian et al, 2005Qian et al, , 2007.…”

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confidence: 99%

“…In addition, HDACIs when combined with retinoids (e.g., ATRA, 9-cis retinoic acid (9-CRA) or 13-cis-retinoic acid (13-CRA)) display enhanced (additive) anticancer activities (Pili et al, 2001;Gediya et al, 2005;Qian et al, 2005Qian et al, , 2007. However, combination antiproliferative studies with the well-known synthetic retinoid, N-(4-hydroxyphenyl)retinamide, (4-HPR) have produced conflicting results.…”

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confidence: 99%

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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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“…14, 15 We also reported recently that combination of SAHA with either retinoids or RAMBAs resulted in additive/synergistic PCA (LNCaP and PC-3 cell lines) growth inhibition in vitro. 16 In continuation of our research in this area, we have discovered improved syntheses of two promising HDIs, 17, 18,19 CI-994, (N-(2aminophenyl)-4-acetylaminobenamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-ylmethoxycarbonyl)aminomethyl]benzamide). Furthermore, we assessed the effects of our novel RAMBAs and retinoids (see Chart 1) in combination with some HDIs in human prostate cancer model systems in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts

Gediya

Belosay

Khandelwal

et al. 2008

Bioorganic & Medicinal Chemistry

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We have developed new, simple and efficient procedures for the synthesis of two promising histone deacetylase inhibitors ((HDIs), CI-994, (N-(2aminophenyl)-4-acetylaminobenamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-ylmethoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80 and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and decrease in the S phase in LNCaP cells. 2 + SAHA treatment effectively downregulated cyclin D1 and cdk4 and up-regulated pro-differentiation cytokeratin 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2 + SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.

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A New Simple and High-Yield Synthesis of Suberoylanilide Hydroxamic Acid and Its Inhibitory Effect Alone or in Combination with Retinoids on Proliferation of Human Prostate Cancer Cells

Cited by 94 publications

References 9 publications

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

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

Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts

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