Pharmacological inhibition of Rho-kinase (ROCK) signaling enhances cisplatin resistance in neuroblastoma cells

Street, Catharine A; Routhier, Alissa A; Spencer, Carrie; Perkins, Ashley Lyn; Masterjohn, Katherine; Hackathorn, Alexander; Montalvo, John; Dennstedt, Emily A; Bryan, Brad Allen

doi:10.3892/ijo_00000781

Cited by 15 publications

(3 citation statements)

References 48 publications

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“…In the present study MTX prominently induced histopathological changes and hepatic tissue injury as found by histopathological examination. This was in agreement with preceding studies [8], which found that MTX can induce hepatic lesions, such as focal fibrosis, congestion, and dilatation of sinusoids with fatty vacuolation, and portal vein inflammation [31], which could be recognized, as the liver is the major site of MTX metabolism into the toxic agent 7-hydroxy-MTX, and the MTX can be stored inside hepatocytes in polyglutamated form, leading to hepatotoxicity [32,33].…”

Section: Discussionsupporting

confidence: 92%

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals

et al. 2022

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Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1β. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique.

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Section: Discussionsupporting

confidence: 92%

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals

et al. 2022

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“…Our preliminary experiments on the effect of blebbistatin on apoptotic cells did show inhibition of water loss, but much more extensive studies would be needed for definitive conclusions. The problem with blebbistatin is that it inhibits apoptosis in general (Xiao et al, 2009;Street et al, 2010;Li et al, 2018;Chai et al, 2019). While such inhibition is compatible with the view that (1) cytoskeletal compression causes dehydration and that (2) dehydration is needed for apoptosis, one cannot claim that blebbistatin inhibits AVD if apoptosis is no longer present.…”

Section: Intracellular Pressurementioning

confidence: 99%

A Reverse-Osmosis Model of Apoptotic Shrinkage

Rana

Model

2020

Front. Cell Dev. Biol.

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The standard theory of apoptotic volume decrease (AVD) posits activation of potassium and/or chloride channels, causing an efflux of ions and osmotic loss of water. However, in view of the multitude of possible channels that are known to support apoptosis, a model based on specific signaling to a channel presents certain problems. We propose another mechanism of apoptotic dehydration based on cytoskeletal compression. As is well known, cytoskeleton is not strong enough to expel a substantial amount of water against an osmotic gradient. It is possible, however, that an increase in intracellular pressure may cause an initial small efflux of water, and that will create a small concentration gradient of ions, favoring their exit. If the channels are open, some ions will exit the cell, relieving the osmotic gradient; in this way, the process will be able to continue. Calculations confirm the possibility of such a mechanism. An increase in membrane permeability for water or ions may also result in dehydration if accompanied even by a constant cytoskeletal pressure. We review the molecular processes that may lead to apoptotic dehydration in the context of this model.

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“…Treatment with ROCK inhibitor Y27632 led to increased migration and mitotic activity in breast, colon and pancreatic cancer cell cultures (12)(13)(14)(15). Others showed that inactivation of ROCK signaling promoted cell survival and attenuated drug-induced apoptosis in leukemia, neuroblastoma and ovarian carcinoma (16)(17)(18), as well as increased cancer cell stemness (19,20). These seemingly contradictory findings may be at least partly attributed to the choice of different cell lines in various studies.…”

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confidence: 99%

ROCK1 and ROCK2 Are Down-regulated in Aggressive and Advanced Skin Melanomas – A Clinicopathological Perspective

et al. 2020

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Background: RhoA and its downstream effectors Rho-associated coiled-coil kinases (ROCK) 1 and 2 are central controllers of cytoskeleton dynamics, and therefore influence cell shape, adhesion and migration. Since modulation of these processes holds promise for an effective anticancer strategy, effects of ROCK inhibition have been evaluated in a number of malignancies. Materials and Methods: Using immunohistochemistry, ROCK1 and ROCK2 expression was semi-quantitatively assessed in 129 patientderived primary melanomas. Results: There was a striking predilection for low melanocytic expression of both kinases in thick, ulcerated and mitogenic tumors, as well as in nodular histological type. ROCK1 and-2 expression in tumor-infiltrating lymphocytes (TILs) was preferentially down-regulated in advanced and aggressive tumors. Moreover, diminished ROCK2 reactivity in melanoma cells and TILs was associated with shorter melanoma-specific and recurrence-free survival. Conclusion: This is the first analysis of ROCK1 and-2 protein expression in clinical melanoma samples and the results indicated the suppression of ROCK signaling in melanocytes of aggressive and late-stage tumors. Functional models that more accurately represent the clinical setting are necessary to dissect the role of ROCK1 and-2 in melanoma. Additionally, our study indicates that ROCK activity in TILs may be involved in the pathogenesis of cancer, and thus merits further investigations.

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Pharmacological inhibition of Rho-kinase (ROCK) signaling enhances cisplatin resistance in neuroblastoma cells

Cited by 15 publications

References 48 publications

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals

A Reverse-Osmosis Model of Apoptotic Shrinkage

ROCK1 and ROCK2 Are Down-regulated in Aggressive and Advanced Skin Melanomas – A Clinicopathological Perspective

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