Showing papers by "Michael B. Sporn published in 2011"
TL;DR: It is shown that pre-treatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell-associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs.
Abstract: Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function. In a previous study, we found that in mice, myeloid-derived suppressor cells (MDSCs) are a source of the free radical peroxynitrite (PNT). Here, we show that pre-treatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell-associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs. This effect was abrogated in MDSCs treated with a PNT inhibitor. In a mouse model of tumor-associated inflammation in which the antitumor effects of antigen-specific CTLs are eradicated by expression of IL-1β in the tumor cells, we determined that therapeutic failure was not caused by more profound suppression of CTLs by IL-1β-expressing tumors than tumors not expressing this proinflammatory cytokine. Rather, therapeutic failure was a result of the presence of PNT. Clinical relevance for these data was suggested by the observation that myeloid cells were the predominant source of PNT in human lung, pancreatic, and breast cancer samples. Our data therefore suggest what we believe to be a novel mechanism of MDSC-mediated tumor cell resistance to CTLs.
301 citations
TL;DR: The original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO) based on oleanolic acid as a starting material is reviewed, as is formation of biotin conjugates for investigation of protein targets.
Abstract: We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress
293 citations
TL;DR: Two triterpenoid compounds that activate the Nrf2/ARE signaling pathway may be useful in the treatment of ALS and significantly attenuated weight loss, enhanced motor performance, and extended the survival of G93A SOD1 mice.
188 citations
TL;DR: It is indicated that Nrf2 is an important cytoprotective mechanism in the retina in response to ischemia-reperfusion injury and suggested that pharmacologic induction of NRF2 could be a new therapeutic strategy for retinal ischemIA-rePerfusion and other retinal diseases.
119 citations
TL;DR: The dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes is demonstrated.
Abstract: Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of pro-inflammatory transcripts with concomitant induction of anti-inflammatory genes including Ptgds and Hsd11b1. Finally, triterpenoids induced oligodendrocyte maturation in vitro and enhanced myelin repair in an LPC-induced non-inflammatory model of demyelination in vivo. These results demonstrate the unique potential of triterpenoid derivatives for the treatment of neuroinflammatory disorders such as MS.
98 citations
TL;DR: In this paper, the putative target profile of one synthetic oleanane triterpenoids (SO), CDDO-Imidazolide, was characterized by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells.
Abstract: New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity.
95 citations
TL;DR: Drugs to prevent cancer are clearly possible despite some early missteps, and the cooperative ethos of decades past will help get us there, says Michael B. Sporn.
Abstract: Drugs to prevent cancer are clearly possible despite some early missteps, says Michael B. Sporn. Restoring the cooperative ethos of decades past will help get us there.
44 citations
TL;DR: Results show that CDDO-Im induces ROS and subsequent DNA damage, thereby facilitating the activation of the DNA damage checkpoint, G2/M arrest, and finally apoptosis in BRCA1-mutated cancer cells.
Abstract: Breast cancer-associated gene 1 (BRCA1) protein plays important roles in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide, CDDO-Im) is a promising anticancer and chemopreventive agent with potent anti-proliferative and apoptotic activities against a wide variety of cancer types. However the mechanisms responsible for the selective apoptotic effects of CDDO-Im in cancer cells remain elusive. In the present work, CDDO-Im induced G2/M arrest and apoptosis in BRCA1-mutated mammary tumor cell lines. Prior to the induction of apoptosis, CDDO-Im induced DNA damage and the phosphorylation of H2AX followed by activation of the DNA damage response. Moreover, CDDO-Im also induced the generation of reactive oxygen species (ROS), which is associated with the induction of DNA damage, in both mouse and human tumor cells containing a BRCA1 mutation. The inhibition of ROS generation by uric acid prevented the induction of DNA damage by CDDO-Im. Furthermore, treatment with CDDO-Im did not induce ROS in non-malignant MCF-10A breast epithelial cells or in E18-14C-27 breast cancer cells with wild-type BRCA1 genes and was not cytotoxic to normal mouse 3T3 fibroblasts, highlighting a selective therapeutic potential of CDDO-Im for BRCA1-associated breast cancer cells. Altogether, our results demonstrate that CDDO-Im induces ROS and subsequent DNA damage, thereby facilitating the activation of the DNA damage checkpoint, G2/M arrest and finally apoptosis in BRCA1-mutated cancer cells. The particular relevance of these findings to the chemoprevention of cancer is discussed.
39 citations
TL;DR: In this article, the effect of synthetic triterpenoids (CDDO-Imidazolide) on liver metastasis was evaluated using B16F1 (mouse melanoma) and HT-29 (human colon carcinoma).
Abstract: Survival following diagnosis of liver metastasis remains poor and improved treatment strategies to combat liver metastases are needed. Synthetic triterpenoids, including 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide or CDDO-Im), have been shown to inhibit primary tumor growth and lung metastasis in experimental models. Oral administration of CDDO-Im results in relatively high liver concentrations, suggesting that CDDO-Im may provide an approach to treatment of liver metastases. Here we assessed the effect of CDDO-Im on liver metastasis, using B16F1 (mouse melanoma) and HT-29 (human colon carcinoma) cells. In vitro, nanomolar concentrations of CDDO-Im arrested proliferation or induced cell death in both cell lines. In vivo, cells were injected via a surgically exposed mesenteric vein to target cells to the liver of mice. Mice were then treated with CDDO-Im (800 mg/kg diet) or vehicle control. Livers were removed at endpoint and metastatic burden was quantified by standard histology. In addition, a novel whole liver magnetic resonance imaging (MRI) technique was used to assess the effect of CDDO-Im on growing metastases as well as on non-dividing, solitary cancer cells present in the same livers. CDDO-Im treatment significantly decreased liver metastasis burden in both HT-29 (n = 8 treated, 10 control) and B16F1 (n = 15 treated, 16 control) injected mice (>60%, P < 0.05), but did not reduce the numbers of solitary B16F1 cancer cells (hypo-intensity) in the same livers (P = 0.9). This study demonstrates that CDDO-Im may be useful for the treatment metastatic liver disease as it successfully inhibits growth of actively proliferating liver metastases.
27 citations
TL;DR: A review of the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO) based on oleanolic acid as a starting material is given in this paper.
Abstract: We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress.
Journal Article•
TL;DR: Drugs to prevent cancer are clearly possible despite some early missteps, and the cooperative ethos of decades past will help get us there, says Michael B. Sporn.
Abstract: Drugs to prevent cancer are clearly possible despite some early missteps, says Michael B. Sporn. Restoring the cooperative ethos of decades past will help get us there.
01 May 2011
TL;DR: Treatment with bardoxolone for 24 weeks in patients with Stage 3b/4 chronic kidney disease and type 2 diabetes resulted in a large increase in eGFR, relative to no change in the placebo group, and significant improvements were also noted in other measured of kidney function, including blood urea nitrogen, serum phosphorus, and serum uric acid relative to placebo.
Journal Article•
TL;DR: Testing the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of ER-negative breast cancer found it significantly increased the age of mice at onset of first tumor by an average of 4.3 weeks.
Abstract: Breast cancer is the most common cancer among women in the United States. The incidence rates of breast cancer are no longer significantly declining, and approximately 40,000 women die from the disease each year. Hence, novel drugs are needed for the prevention and treatment of the disease. Synthetic triterpenoids are a promising new class of compounds with chemopreventive activity in a variety of preclinical cancer models. We tested the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of ER-negative breast cancer. In this mouse model, the polyoma-middle T (PyMT) oncoprotein drives carcinogenesis in the mammary gland. The developing tumors recapitulate key features of the human disease including significant infiltration of tumor-associated macrophages (TAM). Depletion of TAMs has been previously shown to delay tumor progression. PyMT mice were fed CDDO-Me (50 mg/kg diet), starting at 4 weeks of age. CDDO-Me significantly increased the age of mice at onset of first tumor by an average of 4.3 weeks (P Citation Information: Cancer Prev Res 2011;4(10 Suppl):A103.