Intracellular Delivery of the p38 Mitogen-Activated Protein Kinase Inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1<i>H</i>-imidazole] in Renal Tubular Cells: A Novel Strategy to Treat Renal Fibrosis

Prakash, Jai; Sandovici, Maria; Saluja, Vinay; Lacombe, M.; Schaapveld, Roel Q.J.; Borst, Martin H. de; Goor, Harry van; Henning, Robert H.; Proost, Johannes H.; Moolenaar, Frits; Kéri, Gÿorgý; Meijer, Dirk K. F.; Poelstra, Klaas; Kok, Robbert J.

doi:10.1124/jpet.106.106054

Cited by 59 publications

(54 citation statements)

References 32 publications

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“…The absence of cytotoxic effects observed for 17864-ULS-lysozyme is in agreement with previous studies performed with another renal-specific conjugate, ie, SB202190-ULS-lysozyme, directed against a different profibrotic kinase. 25 As anticipated, methionine-modified lysozyme alone was also non-toxic to HK-2 cells (data not shown). Figure 5 shows the plasma disappearance curves of 17864-ULS-lysozyme and sunitinib after a single intravenous injection of the compounds in mice.…”

Section: In Vitro Cytotoxicitymentioning

confidence: 71%

“…11,[19][20][21][22] To avoid these side effects, targeted delivery of sunitinib to the target cells, ie, the proximal tubular cells of the kidneys, is a comprehensive approach. We have shown that small-molecule inhibitors can be delivered to the kidney by conjugation to lysozyme, [23][24][25] a low molecular weight protein that is rapidly filtered through the glomeruli of the kidneys and subsequently taken up at the apical membrane of proximal tubular cells via megalin receptor-mediated internalization. 26 Since sunitinib does not contain functional groups such as hydroxyl or primary amino groups that can be used for the coupling to lysozyme, we designed a sunitinib derivative that can be linked to lysozyme via the platinum (II)-based Universal Linkage System TM (ULS) (Kreatech Diagnostics, Amsterdam, The Netherlands).…”

Section: Introductionmentioning

confidence: 99%

“…Upon intravenous administration, the majority of the targeted drug persisted in the designated cells in the ULS-bound form. 25,28 In the current study, we therefore designed a sunitinib analog which retained its activity in the ULS-bound form, and thus could display its activity as a platinum conjugate upon delivery in the proximal tubular cells of the kidneys.…”

Section: Introductionmentioning

confidence: 99%

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Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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Background: Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis. Methods: A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice. Results: The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects. Conclusion: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.

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Section: In Vitro Cytotoxicitymentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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“…It is noteworthy that the colon of these mice showed normal architecture at the histological analysis. 38 Furthermore, a novel strategy for local delivery of SB has been developed to treat renal fibrosis, 39 indicating that pharmacological manipulation of p38 is emerging as a potential therapeutic tool for a number of human diseases. In this sense, our study might have an even broader interest.…”

Section: Discussionmentioning

confidence: 99%

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

et al. 2006

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Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38a/b kinases. We report that p38a is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38a activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38a as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38a pathway in the treatment of colorectal cancer. Colorectal cancer is a major health concern, with more than 1 000 000 new cases and 500 000 deaths expected worldwide per year.1 Prognostic evaluation is currently based on histological appearance, and there are no molecular markers internationally recognized as standard predictor factors. The conventional therapy involving surgery and adjuvant therapy seems to give rise to improvements in progression-free and overall survival. Nevertheless about 50% of patients die within 5 years owing to metastasis or recurrent disease.2 The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of cell cycle and cell death regulatory pathways in tumor cells in order to identify differential cellular effects of agents that may have a direct impact on cancer therapy.During the last decade, a number of deacetylase inhibitors (DI) have been identified. These DI induce tumor cells to undergo growth arrest, differentiation, and/or apoptosis in culture and in animal models, at doses that seem to be nontoxic and appear to be selective. Butyrate, a DI that is naturally formed in the human colon, is able to reduce the size and the number of tumors in rat models of bowel cancer.3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs).4-6 NaB-mediated cell cycle withdrawal of CRCs appears to be dependent on acetylation of histones and consequent changes in transcription, requiring continuous protein synthesis and the expression of p21. 7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent...

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“…Although the long-term effects of p38 inhibition on the development of diabetic nephropathy have not been elucidated, study have shown that this intervention may attenuate the development of renal glomerular and interstitial lesions in non-diabetic models of kidney disease. 38,39 In an experimental model of diabetic cardiomyopathy, chronic p38 inhibition attenuated the left ventricular dysfunction and prevented cardiac inflammation. 40 In summary, renal cortical p38 MAPK activity and expression was increased in diabetic rats at early stages of nephropathy as well as in animals with advanced disease, as compared with age-matched non-diabetic animals.…”

Section: Renal P38 In Experimental Diabetesmentioning

confidence: 99%

Renal p38 MAP kinase activity in experimental diabetes

Komers

Lindsley

Oyama

et al. 2007

Laboratory Investigation

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Renal cell activity of p38 mitogen-activated protein kinase (p38) is increased in the diabetic milieu. p38 mediates signals relevant for the development of diabetic nephropathy (DN). However, renal p38 in Type 1 diabetes in vivo, particularly in conditions reflecting the differences in metabolic control, and its activity in advanced stages of DN, has received less attention. We examined the p38 pathway in renal cortex of rats with streptozotocin diabetes (4 weeks) with poor (DS), moderate (DM), and intensive (DII) metabolic control, achieved by varying doses of insulin therapy. Renal p38 was also studied in 12-month diabetic rats with established nephropathy (DM12) and compared with age-matched controls. p38 activity (in vitro kinase assay and expression of phosphorylated (active) p38 (P-p38)) was increased in DM and DS rats, as compared with non-diabetic controls, and attenuated by intensive insulin treatment. In all groups, P-p38 was predominantly localized in macula densa cells. Diabetic rats also demonstrated P-p38 immunoreactivity in the distal tubule and glomeruli. Enhanced p38 activity in DS and DM rats was not associated with increases in expression of active mitogen-activated protein kinase 3/6, an activator of p38, but paralleled with increased expression of scaffolding protein transforming growth factor-b-activated protein kinase 1-binding protein 1. Expression of mitogen-activated protein phosphatase-1 (MKP-1), one of the phosphatases involved in inactivation of mitogen-activated protein kinase signaling, was increased in all diabetic groups, irrespective of metabolic control. Renal p38 activation was also detectable in D12 rats with established albuminuria and glomerulosclerosis. In summary, renal cortical p38 activity was increased in diabetic rats at early and advanced stages of nephropathy, as compared with non-diabetic animals, and attenuated by improved metabolic control. p38 activation in diabetes is likely to occur via multiple pathways and cannot be explained by downregulation of MKP-1. KEYWORDS: diabetic nephropathy; hyperglycemia; p38 mitogen-activated protein kinase; proteinuria; signaling High glucose concentrations, and potentially other factors in the diabetic milieu, trigger pathophysiological signals mediated by the activation of specific kinase cascades. Altered activation of mitogen-activated protein (MAP) kinases (MAPK) occurs under these conditions and results in a broad spectrum of acute and long-term effects including mobilization of intracellular calcium and induction of gene expression. 1 In the kidney, such aberrant activation of MAPK cascades may perturb the balance of humoral and cytokine systems responsible for regulating vascular tone, permeability, renal cellular growth, and composition of the extracellular/mesangial matrix (ie, factors associated with the development of diabetic nephropathy). 2,3 p38 mitogen-activated protein kinase (p38), a member of the MAPK family, is activated by a number of stimuli. As a stress-activated kinase, p38 is activated by physical and ch...

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Intracellular Delivery of the p38 Mitogen-Activated Protein Kinase Inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in Renal Tubular Cells: A Novel Strategy to Treat Renal Fibrosis

Cited by 59 publications

References 32 publications

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

Renal p38 MAP kinase activity in experimental diabetes

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