Honokiol, a Polyphenol Natural Compound, Attenuates Cisplatin-Induced Acute Cytotoxicity in Renal Epithelial Cells Through Cellular Oxidative Stress and Cytoskeleton Modulations

Abstract

Cisplatin is a potent anti-cancer drug that has been widely used in the treatment of various cancers; however, cisplatin administration results in severe nephrotoxicity and impedes its clinical applications. In this study, we showed that honokiol, a polyphenol constituent extracted from Magnolia officinalis exhibited a short-term protective effect against cisplatin-induced damages in renal epithelial cells in vitro. The protective effects of honokiol were resulted from the combination of (1) reduced cellular oxidative stress ranging from 53 to 32% reduction during a 24-h incubation, (2) the maintenance of cellular antioxidant capacity and (3) the stabilization of cytoskeletal structure of the kidney epithelial cells. By promoting the polymerization of actin (1.6-fold increase) and tubulin (1.8-fold increase) cytoskeleton, honokiol not only maintained epithelial cell morphology, but also stabilized cellular localizations of tight junction protein Occludin and adhesion junction protein E-Cadherin. With stabilized junction protein complexes and structural polymerized cytoskeleton network, honokiol preserved epithelial cell polarity and morphology and thus reduced cisplatin-induced cell disruption and damages. Our data demonstrated for the first time that honokiol could counteract with cisplatin-induced damages in renal epithelial cells in vitro, future in vivo studies would further validate the potential clinical application of honokiol in cisplatin-based cancer treatments with reduced nephrotoxicity.

Counteracting Cisplatin-Induced Testicular Damages by Natural Polyphenol Constituent Honokiol

“…Moreover, RNAseq analysis using testicular samples from in-vivo experiments was also performed to evaluate mitochondrial antioxidation enzyme activities. Unexpectedly, unlike our earlier report in the kidney [ 17 , 18 ], TAC assay did not show significant changes between groups ( Figure 4 A); however, from RNAseq analysis, mitochondrial antioxidant enzymes including glutathione peroxidase (Gpx), thioredoxin reductase (Txnrd), glutaredoxin (Glrx), peroxiredoxin (Prdx) were downregulated upon cisplatin treatment, and were upregulated when nHNK was given as treatment ( Figure 4 B). These data suggested cisplatin and nHNK altered mitochondrial enzymatic machinery in the testis.…”

“…Besides forming DNA adducts [ 6 ], cisplatin also induces excessive ROS production that disrupts physiological balance of redox and anti-oxidation activities [ 42 ]. We previously showed both in vitro and In Vivo that cisplatin compromised mitochondria total antioxidant capacity, and as a consequence, led to imbalanced mitochondria redox processes and caspase 3-associated apoptosis [ 17 , 18 ]. Other studies also showed cisplatin induced dose-dependent testicular damage, ROS generation and ER stress in rat testis [ 10 , 43 , 44 ].…”

“…On the other hand, the non-enzymatic antioxidants, such as vitamin E, vitamin C, carotene, zinc and taurine can also act as radical scavenging agents or cofactors for non-enzymatic anti-oxidation activities [ 13 , 17 ]. Among non-enzymatic antioxidants, honokiol (HNK), a natural compound of polyphenol, has been shown to attenuate cisplatin-induced renal damages through the reduction of cellular oxidative stress and maintenance of the renal epithelium cytoskeleton [ 17 , 18 ]; moreover, HNK has been shown to reduce torsion-induced acute testicular injury via the reduction of excessive ROS production after ischemia-reperfusion injury [ 19 ]. Based on these studies, HNK is considered an effective scavenger for both superoxide and peroxyl radicals [ 20 , 21 ].…”

Dietary Chrysin Suppresses Formation of Actin Cytoskeleton and Focal Adhesion in AGE-Exposed Mesangial Cells and Diabetic Kidney: Role of Autophagy

“…A recent study shows that salvianolic acid A inhibits renal cytoskeletal dysfunction through inhibiting the AGE–RAGE signaling, thus effectively ameliorating early-stage DN [44]. The polyphenol honokiol counteracts with cisplatin-induced cytoskeletal structure disruption in renal epithelial cells and preserves epithelial cell polarity and morphology [45]. Our previous study found that chrysin, a naturally-occurring flavonoid, inhibited AGE-induced kidney fibrosis in renal mesangial cells and diabetic kidneys through inhibition of AGE–RAGE activation, contributing to blockade of glucose-mediated AGE-associated glomerulosclerosis and fibrosis [34].…”

Honokiol ameliorates angiotensin II‐induced hypertension and endothelial dysfunction by inhibiting HDAC6‐mediated cystathionine γ‐lyase degradation

“…47 HNK was shown to alleviate cytotoxic damages of renal epithelial cells by promoting actin and tubulin polymerization and tubulin bundle formation. 50 This suggested that HNK may contribute to enhanced cytoskeletal integrity by inhibiting HDAC6. Moreover, our current evidence is reminiscent of our previous results obtained using tubastatin A, the well-established HDAC6 inhibitor.…”