Nanoparticulated Honokiol Mitigates Cisplatin-Induced Chronic Kidney Injury by Maintaining Mitochondria Antioxidant Capacity and Reducing Caspase 3-Associated Cellular Apoptosis

Abstract

Cisplatin is a potent anti-cancer drug, however, its accompanied organ-toxicity hampers its clinical applications. Cisplatin-associated kidney injury is known to result from its accumulation in the renal tubule with excessive generation of reactive oxygen species. In this study, we encapsulated honokiol, a natural lipophilic polyphenol constituent extracted from Magnolia officinalis into nano-sized liposomes (nanosome honokiol) and examined the in vivo countering effects on cisplatin-induced renal injury. We observed that 5 mg/kg body weight. nanosome honokiol was the lowest effective dosage to efficiently restore renal functions of cisplatin-treated animals. The improvement is likely due the maintenance of cellular localization of cytochrome c and thus preserves mitochondria integrity and their redox activity, which as a consequence, reduced cellular oxidative stress and caspase 3-associated apoptosis. These improvements at the cellular level are later reflected on the observed reduction of kidney inflammation and fibrosis. In agreement with our earlier in vitro study showing protective effects of honokiol on kidney cell lines, we demonstrated further in the current study, that nanosuspension-formulated honokiol provides protective effects against cisplatin-induced chronic kidney damages in vivo. Our findings not only benefit cisplatin-receiving patients with reduced renal side effects, but also provide potential alternative and synergic solutions to improve clinical safety and efficacy of cisplatin treatment on cancer patients.

Counteracting Cisplatin-Induced Testicular Damages by Natural Polyphenol Constituent Honokiol

“…Animals were given water and standard mice lab chow (Oriental yeast, Tokyo, JP) ad libitum. Preparation of nanosized liposome-encapsulated honokiol (nHNK) were described earlier, qualitative and quantitative characterization of nNNK was carried out at the department of chemistry at National Taiwan University (NTU Mass Spectrometry Platform) and described earlier [ 17 , 22 ]. Animals were randomly allocated into 4 experimental groups (n = 10–12 for each group) and cisplatin-induced testicular injury mouse model was established as summarized in Figure S2A and described as follow.…”

“…nHNK (blue closed circle, 100 μL volume) as indicated in the G2. Determination of nanosome honokiol tissue distribution in reproductive organs was carried out as described earlier [ 17 , 22 ].…”

“…For the enzymatic anti-oxidation mechanism, superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) are critical for testicular redox activity [ 15 , 16 ]. 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 ].…”

“…Although HNK might be effective on reducing cisplatin-induced OS, its lipophilic property restrains its bioavailability to tissue. To overcome this natural chemical solubility barrier of HNK, we encapsulated HNK into nanosized liposome (nanosome honokiol, nHNK) as described earlier to increase its bio-distribution and bio-availability [ 17 , 22 ]. This liposome-encapsulation approach has been shown to exhibit synergic and beneficial effects on anti-cancer ability when used in combination with cisplatin [ 23 , 24 , 25 ], which allows for the slow release of HNK into the body that prolongs its anti-oxidation effects in vivo.…”

Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment

“…Delivery of HNK using mPEG-PLA/vitamin E-TPGS micelles via intravenous route shows lower toxicity and high efficacy 55 . Nanoencapsulation of HNK improves cisplatin-induced pathological changes via reducing cellular oxidative damage and maintaining cellular localization of mitochondrial enzyme cytochrome C 56 . Another interesting approach was to develop self-assembled microbubbles and these honokiol-loaded poly(ε-caprolactone)-poly(ethylene glycol)poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) microbubbles (HK-PCEC-MB) efficiently inhibit cisplatin-resistant ovarian cancer in vivo 57 .…”