Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells

Uchiyama, Hiroo; Tsujimoto, Masayuki; Shinmoto, Tadakazu; Ogino, Hitomi; Oda, Tomoko; Yoshida, Takuya; Furukubo, Taku; Yamakawa, Tomoyuki; Tachiki, Hidehisa; Minegaki, Tetsuya; Nishiguchi, Kohshi

doi:10.3390/toxins6092612

Cited by 5 publications

(8 citation statements)

References 32 publications

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“…These concentrations have been selected based on a review of literature that described the in vitro experiments of statin-induced myotoxicity. 49 , 50 , 51 , 52 , 53 , 54 …”

Section: Discussionmentioning

confidence: 99%

The role of acid-base imbalance in statin-induced myotoxicity

Taha

Moor

Barrett

et al. 2016

Translational Research

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Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are commonly prescribed for elderly patients who have multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. These patients are at risk of developing acid-base imbalance. In the present study, the effect of disturbances in acid-base balance on the interconversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8–7.8. The effects of such interconversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (SVL; ∼87% and 99%, respectively) and pravastatin lactone (PVL; ∼98% and 99%, respectively) were converted to the active hydroxy acid forms after 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic SVL was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared with more hydrophilic simvastatin hydroxy acid, PVL, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionized hydroxy acid form. Consequently, our results suggest that comorbidities associated with acid-base imbalance can play a substantial role in the development and potentiation of statin-induced myotoxicity.

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“…These concentrations have been selected based on a review of literature that described the in vitro experiments of statin-induced myotoxicity. 49 , 50 , 51 , 52 , 53 , 54 …”

Section: Discussionmentioning

confidence: 99%

The role of acid-base imbalance in statin-induced myotoxicity

Taha

Moor

Barrett

et al. 2016

Translational Research

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“…To determine if metabolic intermediates of the mevalonate pathway or LDL treatment revert the cells’ atorvastatin-sensitive phenotype, the statin-sensitive cancer cell line HOP-92 was seeded in 12-well plates at a density of 1 × 10 5 cells/mL (1 mL/well), incubated overnight, and then treated with 10 μM atorvastatin and various concentrations of R-mevalonic acid (10–50 μM; Sigma-Aldrich, St. Louis, MO), ubiquinone (25–200 μM; Wako, Osaka, Japan), dolichol (75–300 μM; Avanti Polar Lipids, Alabaster, AL), squalene (10–100 μM; Wako), FPP (1–25 μM; Echelon, Salt Lake City, UT), GGPP (1–25 μM; Sigma-Aldrich), or LDL (50–200 μg/mL; Alfa Aesar, Ward Hill, MA) for 48 hours. We chose the doses of each substrate according to published references [ 53 , 54 ]. In select experiments, we photographed these cells with a phase-contrast microscope to capture any morphological changes.…”

Section: Methodsmentioning

confidence: 99%

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

et al. 2018

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HMG-CoA reductase (HMGCR) inhibitors, statins, are potent cholesterol reducing drugs that exhibit anti-tumor effects in vitro and in animal models, including attenuation of metastasis formation, and their use correlates with reduced cancer-specific mortality in retrospective human cohort studies. However, E-cadherin expressing epithelial- and mixed epithelial-mesenchymal cancer cell lines (reflective of primary and outgrowing metastatic tumor cells, respectively) require higher statin concentrations than mesenchymal-like tumor cells (reflective of in-circulation metastatic tumor cells) to achieve the same degree of growth inhibition. Here, we show that attenuation of HMGCR expression in the presence of atorvastatin leads to stronger growth inhibition than dual target blockade of the mevalonate pathway in relatively statin resistant cell lines, mainly through inhibition of protein prenylation pathways. Thus, combined inhibition of the mevalonate pathway's rate-limiting enzyme, HMGCR, can improve atorvastatin's growth inhibitory effect on epithelial- and mixed mesenchymal-epithelial cancer cells, a finding that may have implications for the design of future anti-metastatic cancer therapies.

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“…We had previously shown that statin-induced cytotoxicity in differentiated RD cells was augmented by pre-treatment with uremic toxins—hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indole-3-acetic acid, and 3-indoxyl sulfate, whereas cisplatin-induced cytotoxicity was not affected by pre-treatment with uremic toxins [ 6 ]. In this study, simvastatin-induced apoptosis and cytotoxicity was greater in US cells than in NS cells ( Table 1 and Figure 1 ), and here, we found that simvastatin-induced cytotoxicity was similarly augmented in US cells.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, cytotoxicity associated with losartan and cisplatin was lower in US cells than NS cells ( Table 1 ). The effect of long-time exposed with US on cisplatin-induced cytotoxicity in RD cells was different from effect of pre-treatment with uremic toxins [ 6 ]. It is possible that the decrease in cisplatin-induced cytotoxicity in US cells was due to serum components apart from uremic toxins.…”

Section: Discussionmentioning

confidence: 99%

“…The frequency of rhabdomyolysis in ESKD patients may be higher than that in patients with normal kidney function. Recently, we reported that uremic toxins accumulated in ESKD patients is, at least in part, associated with enhancement of statin-induced cytotoxicity via small G-protein geranylgeranylation [ 6 ]. In statin users, severe vitamin D deficiency that occurs in ESKD patients also appear to be one of risk factors for myalgia which is an initial symptom of rhabdomyolysis [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells

Uchiyama

Tsujimoto

Shimada

et al. 2018

Toxins

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Patients with end-stage kidney disease (ESKD) are at higher risk for rhabdomyolysis induced by statin than patients with normal kidney function. Previously, we showed that this increase in the severity of statin-induced rhabdomyolysis was partly due to uremic toxins. However, changes in the quantity of various trace elements in ESKD patients likely contribute as well. The purpose of this study is to determine the effect of trace elements on statin-induced toxicity in rhabdomyosarcoma cells exposed to uremic serum (US cells) for a long time. Cell viability, apoptosis, mRNA expression, and intracellular trace elements were assessed by viability assays, flow cytometry, real-time RT-PCR, and ICP-MS, respectively. US cells exhibited greater simvastatin-induced cytotoxicity than cells long-time exposed with normal serum (NS cells) (non-overlapping 95% confidence intervals). Intracellular levels of Mg, Mn, Cu, and Zn were significantly less in US cells compared to that in NS cells (p < 0.05 or 0.01). Pre-treatment with TPEN increased simvastatin-induced cytotoxicity and eliminated the distinction between both cells of simvastatin-induced cytotoxicity. These results suggest that Zn deficiencies may be involved in the increased risk for muscle complaints in ESKD patients. In conclusion, the increased severity of statin-induced rhabdomyolysis in ESKD patients may be partly due to trace elements deficiencies.

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Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells

Cited by 5 publications

References 32 publications

The role of acid-base imbalance in statin-induced myotoxicity

The role of acid-base imbalance in statin-induced myotoxicity

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells

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