Abstract
Doxazosin and carvedilol have been evaluated as an alternative treatment against chronic liver lesions and for their possible role during the regeneration of damage caused by liver fibrosis in a hamster model. However, these drugs have been reported to induce morphological changes in hepatocytes, affecting the recovery of liver parenchyma. The effects of these α/𝛽 adrenoblockers on the viability of hepatocytes are unknown. Herein, we demonstrate the protective effect of curcumin against the possible side effects of doxazosin and carvedilol, drugs with proven antifibrotic activity. After pretreatment with 1 μM curcumin for 1 h, HepG2 cells were exposed to 0.1–25 μM doxazosin or carvedilol for 24, 48, and 72 h. Cell viability was assessed using the MTT assay and SYTOX green staining. Morphological changes were detected using the hematoxylin and eosin (H&E) staining and scanning electron microscopy (SEM). An expression of apoptotic and oxidative stress markers was analyzed using reverse transcription-quantitative PCR (RT-qPCR). The results indicate that doxazosin decreases cell viability in a time- and dose-dependent manner, whereas carvedilol increases cell proliferation; however, curcumin increases or maintains cell viability. SEM and H&E staining provided evidence that doxazosin and carvedilol induced morphological changes in HepG2 cells, and curcumin protected against these effects, maintaining the morphology in 90% of treated cells. Furthermore, curcumin positively regulated the expression of Nrf2, HO-1, and SOD1 mRNAs in cells treated with 0.1 and 0.5 μM doxazosin. Moreover, the Bcl-2/Bax ratio was higher in cells that were treated with curcumin before doxazosin or carvedilol. The present study demonstrates that curcumin controls doxazosin- and carvedilol-induced cytotoxicity and morphological changes in HepG2 cells possibly by overexpression of Nrf2.
Highlights
The antihypertensive doxazosin, an α-1 adrenergic receptor blocker, has been used to treat benign prostatic hyperplasia and in trials of cardiovascular metabolic disorders as a lipid-lowering agent to prevent heart attack [1, 2]
The apoptosis of cultured cardiomyocytes occurs dose dependently at concentrations ranging from 0.1 to 50 μmol/L of doxazosin; this result was reported based on quinazoline, which reacts with different cell targets and leads
To analyze whether the morphological changes in HepG2 cells treated with doxazosin and carvedilol corresponded to an apoptosis process and the cells were possibly undergoing drug-activated oxidative stress, we evaluated expression of apoptosis and oxidative stress markers, including Bax, Bcl-2, nuclear factor 2 (Nrf2), Keap1, heme oxygenase-1 (HO-1), and SOD
Summary
The antihypertensive doxazosin, an α-1 adrenergic receptor blocker, has been used to treat benign prostatic hyperplasia and in trials of cardiovascular metabolic disorders as a lipid-lowering agent to prevent heart attack [1, 2]. Doxazosin is known to induce apoptosis in prostate cancer cells [2]. Doxazosin has been reported to induce apoptosis in cultured cardiomyocytes, possibly independently of blocking α-1 adrenergic receptors [1]. The apoptosis of cultured cardiomyocytes occurs dose dependently at concentrations ranging from 0.1 to 50 μmol/L of doxazosin; this result was reported based on quinazoline, which reacts with different cell targets and leads. The serum doxazosin concentration reaches 0.122 and 0.244 μmol/L with doxazosin doses of 8 and 16 mg, respectively [1]. Carvedilol (1-[carbazole-(4)-oxyl]-3-[(2-methoxy-phenoxyethyl)-amino]-2-propanol) is a nonselective β-adrenergic antagonist with vasodilator properties that shows an antagonist activity against the α-1 receptors. Carvedilol has been reported to act as a potent antioxidant [3]
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