Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients. Using RNAi, we provide the first in vivo evidence in mammals to support LDH as the key enzyme responsible for converting glyoxylate to oxalate. In addition, we demonstrate that reduction of hepatic LDH achieves efficient oxalate reduction and prevents calcium oxalate crystal deposition in genetically engineered mouse models of PH types 1 (PH1) and 2 (PH2), as well as in chemically induced PH mouse models. Repression of hepatic LDH in mice did not cause any acute elevation of circulating liver enzymes, lactate acidosis, or exertional myopathy, suggesting further evaluation of liver-specific inhibition of LDH as a potential approach for treating PH1 and PH2 is warranted.
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutations of alanine-glyoxylate aminotransferase (AGT), a key hepatic enzyme in the detoxification of glyoxylate arising from multiple normal metabolic pathways to glycine. Accumulation of glyoxylate, a precursor of oxalate, leads to the overproduction of oxalate in the liver, which accumulates to high levels in kidneys and urine. Crystalization of calcium oxalate (CaOx) in the kidney ultimately results in renal failure. Currently, the only treatment effective in reduction of oxalate production in patients who do not respond to high-dose vitamin B6 therapy is a combined liver/kidney transplant. We explored an alternative approach to prevent glyoxylate production using Dicer-substrate small interfering RNAs (DsiRNAs) targeting hydroxyacid oxidase 1 (HAO1) mRNA which encodes glycolate oxidase (GO), to reduce the hepatic conversion of glycolate to glyoxylate. This approach efficiently reduces GO mRNA and protein in the livers of mice and nonhuman primates. Reduction of hepatic GO leads to normalization of urine oxalate levels and reduces CaOx deposition in a preclinical mouse model of PH1. Our results support the use of DsiRNA to reduce liver GO levels as a potential therapeutic approach to treat PH1.
CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET-and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration. Mol Cancer Ther; 12(6); 925-36. Ó2013 AACR.
Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver damage. Diet control is frequently utilized to manage the potentially dangerous hypoglycemia, but there is currently no effective pharmacological treatment for preventing hepatomegaly and concurrent liver metabolic abnormalities, which could lead to fibrosis, cirrhosis, and hepatocellular adenoma or carcinoma. In this study, we demonstrate that inhibition of glycogen synthesis using an RNAi approach to silence hepatic Gys2 expression effectively prevents glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III. Mechanistically, reduction of accumulated abnormally structured glycogen prevents proliferation of hepatocytes and activation of myofibroblasts as well as infiltration of mononuclear cells. Additionally, we show that silencing Gys2 expression reduces hepatic steatosis in a mouse model of GSD type Ia, where we hypothesize that the reduction of glycogen also reduces the production of excess glucose-6-phosphate and its subsequent diversion to lipid synthesis. Our results support therapeutic silencing of GYS2 expression to prevent glycogen and lipid accumulation, which mediate initial signals that subsequently trigger cascades of long-term liver injury in GSDs.
The Hsp90 chaperone is required for the maturation of signal transduction clients, including many kinases and nuclear steroid hormone receptors. The binding and hydrolysis of ATP by Hsp90 drive conformational rearrangements in three structure domains. Two intrinsically disordered regions of Hsp90 located between these domains and at the C terminus have traditionally been considered to impart flexibility. We discovered that the charged nature of these acid-rich disordered regions imparts a solubility-promoting function to Hsp90 that is important for its cellular activity in yeast. Both the solubility-promoting function and ATPase activity must occur in the same Hsp90 molecule in order to support robust growth, suggesting that the solubility-promoting function is required during the ATP-driven client maturation process. Expression of model clients together with Hsp90 variants indicated interdependent solubilities mediated by the aggregation propensities of both the client and Hsp90. We propose a model whereby the charge-rich disordered regions of Hsp90 serve a solubility-promoting function important for complexes with aggregation-prone clients. These findings demonstrate a novel biological function of the intrinsically disordered regions in Hsp90 and provide a compelling rationale for why their charged properties are conserved throughout eukaryotic evolution.
Histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K) inhibitors have each emerged as promising anti-cancer therapeutics that may target not only cancer cells but also their microenvironment. We have developed a strategy to simultaneously inhibit HDAC- and PI3K-dependent signaling with a single small molecule, CUDC-907. In this study, we report that CUDC-907 induces apoptosis and G2/M arrest in hematological cancer cells. CUDC-907 also impairs cytokine and chemokine production, in association with inhibition of AKT and STAT phosphorylation. Moreover, we demonstrate that CUDC-907 reduces hypoxia-induced HIF-1a expression in cancer cells and VEGF-induced tube formation in endothelial cells, suggesting potential anti-angiogenic activity. With its integrated HDAC and PI3K inhibitory activity, CUDC-907 may thus offer improved therapeutic benefit through simultaneous suppression of cancer cell proliferation and perturbation of their protective microenvironment. These studies provide support for the clinical development of CUDC-907 in hematological malignancies. A Phase I study in patients with lymphoma or multiple myeloma is ongoing. Disclosures: Wang: Curis Inc.: Employment. Pursell:Curis Inc.: Employment. Ma:Curis Inc.: Employment. Atoyan:Curis Inc.: Employment. Samson:Curis Inc.: Employment. Borek:Curis Inc.: Employment. DellaRocca:Curis Inc.: Employment. Yin:Curis Inc.: Employment. Wang:Curis Inc.: Employment. Zifcak:Curis Inc.: Employment. Xu:Curis Inc.: Employment. Voi:Curis Inc.: Employment. Lai:Curis Inc.: Employment.
MYC and CTNNB1 are well-characterized drivers of numerous tumor types. Human and preclinical genetic evidence suggest that pharmacological intervention to reduce transactivation of MYC and CTNNB1-regulated genes would yield therapeutic benefit to many cancer patients. Since the proteins encoded by these genes are challenging to target via conventional modalities, progress in new therapeutic agents has been slow despite decades of research. RNA interference technology has enabled the inhibition of previously-undruggable genetic targets at the mRNA level, and has advanced to clinical development for several indications. DCR-MYC is a Phase I-stage lipid nanoparticle (LNP)-formulated Dicer substrate siRNA (DsiRNA), representing a potent class of RNAi triggers being developed by Dicerna Pharmaceuticals. Here we describe new preclinical data that increase our understanding of the parameters that impact tumor delivery and activity of DsiRNA. We demonstrate that the cationic lipid and PEG-lipid components of Dicerna's unique EnCore LNP platform can be modulated to improve delivery of DsiRNA to both orthotopic and spontaneous liver tumors, as well as xenograft tumors of diverse non-hepatic tissue origin. Characterization of LNP formulations with respect to plasma PK, tissue exposure and target mRNA knockdown was employed towards understanding the pharmacology of LNP-mediated tumor delivery. Citation Format: Marc Abrams, Shanthi Ganesh, Bo Ying, Girish Chopda, Utsav Saxena, Anee Shah, Martin Koser, Rokhand Arvan, Dongyu Chen, Serena Shui, Rohan Diwanji, Wei Zhou, Benjamin Holmes, Boyoung Kim, Hailin Yang, Mihir Patel, Wendy Cyr, Wendy Cyr, Natalie Pursell, Nicole Avitahl-Curtis, Hank Dudek, Cheng Lai, Weimin Wang, Bob D. Brown. EnCore-LNP mediated tumor delivery of MYC and CTNNB1 Dicer Substrate RNAs (DsiRNAs). [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B20.
<p>PDF file - 178K, Changes in live cell numbers induced by the treatment of CUDC-101, erlotinib, or vorinostat in conditions used in the migration and invasion assays.</p>
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