Showing papers by "Michael B. Sporn published in 2017"
TL;DR: These drugs suppressed the production of nitric oxide and a variety of inflammatory cytokines, including IL-6, CCL2, and GM-CSF, in both immune and pancreatic cancer cells in vitro.
97 citations
TL;DR: It is suggested that the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment, and not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs.
Abstract: Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143-56. ©2017 AACR.
22 citations
TL;DR: It is indicated that SO are a new class of immunomodulatory drugs and support further studies investigating this class of agents as potential adjunctive therapy for severe malaria.
Abstract: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection associated with high mortality and neurocognitive impairment in survivors. New anti-malarials and host-based adjunctive therapy may improve clinical outcome in CM. Synthetic oleanane triterpenoid (SO) compounds have shown efficacy in the treatment of diseases where inflammation and oxidative stress contribute to pathogenesis. A derivative of the SO 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), CDDO-ethyl amide (CDDO-EA) was investigated for the treatment of severe malaria in a pre-clinical model. CDDO-EA was evaluated in vivo as a monotherapy as well as adjunctive therapy with parenteral artesunate in the Plasmodium berghei strain ANKA experimental cerebral malaria (ECM) model. CDDO-EA alone improved outcome in ECM and, given as adjunctive therapy in combination with artesunate, it significantly improved outcome over artesunate alone (p = 0.009). Improved survival was associated with reduced inflammation, enhanced endothelial stability and blood–brain barrier integrity. Survival was improved even when administered late in the disease course after the onset of neurological symptoms. These results indicate that SO are a new class of immunomodulatory drugs and support further studies investigating this class of agents as potential adjunctive therapy for severe malaria.
17 citations
TL;DR: 4 rexinoids are reviewed for their ability to suppress proliferation of cancer cells, to inhibit activation of inflammatory cells of the tumor microenvironment, and to prevent carcinogenesis in animal models relevant to human disease.
Abstract: Rexinoids are selective ligands for the nuclear receptors known as RXRs. They do not bind to the receptors for all-trans-retinoic acid (RARs). Many new rexinoids have been synthesized and then assayed for their ability to suppress proliferation of cancer cells, to inhibit activation of inflammatory cells of the tumor microenvironment, and to prevent carcinogenesis in animal models relevant to human disease. Here we review the literature on the effects of 4 such rexinoids: bexarotene, LG100268, LG101506, and NRX194204. These rexinoids also have potent synergistic effects when used in combination with other active pharmacological agents, and practical clinical applications would benefit from these actions.
16 citations
TL;DR: Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro and are reported to be analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1.
Abstract: We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via “abnormal Beckmann” rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.
9 citations
TL;DR: A series of new rexinoids were synthesized and screened them for their ability to inhibit nitric oxide (NO) production in RAW264, a study of macrophage-like cells stimulated with LPS that found them to be selective ligands for retinoid X receptors (RXR).
Abstract: Lung cancer remains the leading cause of cancer deaths around the world. It is estimated that there will be over 150,000 deaths in the United States alone from this disease every year. With no significant improvement in 5 year survival rates over the past 30 years, effective prevention or early intervention is a promising approach to reduce the high mortality of lung cancer. Rexinoids are selective ligands for retinoid X receptors (RXR), which regulate the expression of a wide variety of genes. As transcription factors, rexinoids play important roles in proliferation, differentiation, and apoptosis, which are highly relevant in cancer. Bexarotene is the only synthetic rexinoid that has been approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. It has also been tested in various clinical trials for lung cancer and breast cancer. However, Bexarotene is not potent or selective enough for RXRs, causing limited efficacy and unacceptable toxicities. Therefore, we synthesized a series of new rexinoids and screened them for their ability to inhibit nitric oxide (NO) production in RAW264.7 macrophage-like cells stimulated with LPS. Several of these compounds inhibited NO production at nanomolar concentrations. Based on this screening and other in vitro assays, two new rexinoids were chosen for in vivo testing. Female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg). One week later, the mice were fed control diet or rexinoids in diet (40-80 mg/kg diet) for 16 weeks. Tumor number, size and histopathology were then evaluated. All of the rexinoids reduced the number and size of the lung tumors. However, Bexarotene only reduced the average number of tumors by 8-17%, while a new pyrimidine-analog of Bexarotene—henceforth, pyrimidine-Bexarotene—reduced the number of tumors by 24-28%. The average tumor burden on lung sections was also reduced by pyrimidine-Bexarotene by 59% compared to the controls (from 0.47 ± 0.19 mm 3 in the control group to 0.19 ± 0.05 mm 3 in the treated group). In contrast, average tumor burden was 0.35 ± 0.08 mm 3 in the group treated with Bexarotene, a reduction of 26%. Notably, the percentage of high grade tumors (both histological and nuclear characteristics) were significantly (p Citation Format: Di Zhang, Ana S. Leal, Sarah E. Carapellucci, Kayla Zydeck, Nicole Chaaban, Michael B. Sporn, Carl E. Wagner, Karen T. Liby. Evaluation of new rexinoids for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2017-2245
2 citations