.Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer By Gao, Xiaohua; Deeb, Dorrah; Liu, Yongbo; Arbab, Ali S.; Divine, George W.; Dulchavsky, Scott A.; Gautam, Subhash C.From Cancers (Basel). 2011; 3(3): 3353-3369
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a synthetic analog of oleanolic acid, and its C28 methyl ester derivative (CDDO-Me), have shown potent antitumorigenic activity against a wide range of cancer cell lines, including prostate cancer cells in vitro, and inhibited the development of liver and lung cancer in vivo. In the present study, we examined the efficacy of CDDO-Me in preventing the development and progression of prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model. CDDO-Me inhibited the growth of murine TRAMPC-1 prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. ...
.Reisman SA, Chertow GM, Hebbar S, Vaziri ND, Ward KW, Meyer CJ.Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney.
J Am Soc Nephrol. 2012 Aug 2.
Inflammation and oxidative stress are hallmarks and mediators of the progression of CKD. Bardoxolone methyl, a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant and anti-inflammatory response, increases estimated GFR and decreases BUN, serum phosphorus, and uric acid concentrations in patients with moderate to severe CKD. However, it also increases albuminuria, which is associated with inflammation and disease progression. Therefore, we investigated whether this bardoxolone methyl-induced albuminuria may result from the downregulation of megalin, a protein involved in the tubular reabsorption of albumin and lipid-bound proteins. Administration of bardoxolone methyl to cynomolgus monkeys significantly decreased the protein expression of renal tubular megalin, which inversely correlated with the urine albumin-to-creatinine ratio. Moreover, daily oral administration of bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathologic findings but did reduce serum creatinine and BUN, as observed in patients with CKD. Finally, the bardoxolone methyl-induced decrease in megalin corresponded with pharmacologic induction of renal Nrf2 targets, including NAD(P)H:quinone oxidoreductase 1 enzyme activity and glutathione content. This result indicates that Nrf2 may have a role in megalin regulation. In conclusion, these data suggest that the increase in albuminuria that accompanies bardoxolone methyl administration may result, at least in part, from reduced expression of megalin, which seems to occur without adverse effects and with strong induction of Nrf2 targets.
.McCullough PA, Ali S.
Cardiac and renal function in patients with type 2 diabetes who have chronic kidney disease: potential effects of bardoxolone methyl.
Drug Des Devel Ther. 2012;6:141-9.
The intracellular and tissue balance of oxidant and antioxidant forces is a potential therapeutic target for a variety of agents in the treatment of complications due to chronic disease including diabetes mellitus and hypertension. There are a myriad of processes controlled at the level of genes, transcription factors, and protein messages that work to control the normal use of oxidative reactions within cells. Loss of control of these processes may lead to reversible dysfunction in many cell lines including the podocyte, renal tubular cells, and cardiac myocytes. Bardoxolone methyl is a novel nuclear regulator factor (Nrf-2) activator which works to tip the balance of effects towards antioxidation and as an observation made serendipitously, improves renal filtration function in humans after approximately 12 weeks of therapy. The improvement in estimated glomerular filtration can be up to 30% in those with stage 3 and 4 chronic kidney disease. However, experimental evidence suggests there may be a consequence of relative hyperfiltration in diseased kidneys as well as potential adverse effects on skeletal and cardiac myocytes. Only large, prospective randomized trials with carefully collected and adjudicated clinical outcomes will inform the research community on the therapeutic risks and benefits of this important new agent.
A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy.
Expert Opin Drug Metab Toxicol. 2012 Aug;8(8):1015-22.
Introduction: The coordinated activation of Nrf-2-dependent signaling pathway is currently being investigated in a range of chronic diseases. Bardoxolone methyl is a potent, orally bioavailable Nrf-2 agonist. In a recent 52-week study, treatment with bardoxolone methyl improved renal function in patients with chronic kidney disease (CKD) and type 2 diabetes. This improvement was sustained for the duration of the treatment. Such agonists potentially offer new options for the complex management of renal impairment. Areas covered: A literature search was performed to analyze the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bardoxolone methyl in both healthy volunteers and patients. Updated information about bardoxolone methyl, either after single administration or after chronic administration is also included. A special focus has been put on the putative mechanisms of action and potential toxicity profiles as well as an ongoing trials in patients with CKD and type 2 diabetes. Expert opinion: The development of an agent that leads to sustained improvement in renal function comes as a welcome relief to the millions of individuals with diabetes and CKD. However, much remains to be established regarding its actions in a complex and pleiotropic signalling cascade. Other triterpenoids with different PK/PD profiles are currently under development.
.Rojas-Rivera J, Ortiz A, Egido J.
Antioxidants in kidney diseases: the impact of bardoxolone methyl.
Int J Nephrol. 2012;2012:321714.
Drugs targeting the renin-angiotensin-aldosterone system (RAAS) are the mainstay of therapy to retard the progression of proteinuric chronic kidney disease (CKD) such as diabetic nephropathy. However, diabetic nephropathy is still the first cause of end-stage renal disease. New drugs targeted to the pathogenesis and mechanisms of progression of these diseases beyond RAAS inhibition are needed. There is solid experimental evidence of a key role of oxidative stress and its interrelation with inflammation on renal damage. However, randomized and well-powered trials on these agents in CKD are scarce. We now review the biological bases of oxidative stress and its role in kidney diseases, with focus on diabetic nephropathy, as well as the role of the Keap1-Nrf2 pathway and recent clinical trials targeting this pathway with bardoxolone methyl.