<p>Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity</p>

Abstract

Background: Cisplatin (CDDP), a widely used chemotherapeutic agent against hepatocellular carcinoma (HCC), faces severe resistance and hepatotoxicity problems which can be alleviated through combination therapy. Purpose: The objective of this study was to develop a pH-dependent calcium carbonate nano-delivery system for the combination therapy of CDDP with oleanolic acid (OA). Methods: A microemulsion method was employed to generate lipid coated cisplatin/oleanolic acid calcium carbonate nanoparticles (CDDP/OA-LCC NPs), and the loading concentration of CDDP and OA was measured by atomic absorption spectroscopy and HPLC respectively.Transmission electron microscopy (TEM) was used to examine the nanoparticles morphology while its pH dependent release characteristics were investigated through in vitro release study. Cellular uptake was examined through a fluorescence microscopy. Apoptotic assays and western blot analysis were conducted to explore the synergistic apoptotic effect of OA on CDDP against HCC cells. The hepatoprotective of OA for CDDP was evaluated through H&E staining. Results: TEM analysis revealed nanoparticles spherical shape with an average particle size of 206±15 nm, and the overall entrapment efficiency was 63.70%±3.9%. In vitro drug release study confirmed the pH-dependent property of the formulation, with the maximum CDDP release of 70%±4.6% at pH 5.5, in contrast to 28%±4.1% CDDP release at pH 7.4. Annexin V-FITC/PI assay and cell cycle analysis confirmed that CDDP and OA synergistically promoted greater HepG2 cells apoptosis for the CDDP/OA-LCC NPs as compared to their individual free drug solutions and NPs-treated groups. Western blot analysis also proved that CDDP/OA-LCC NPs induced the apoptosis by enhancing the proapoptotic protein expressions through downregulating P13K/AKT/mTOR pathway and upregulating p53 proapoptotic pathway. OA helped CDDP to overcome the resistance by downregulating the expression of proteins like XIAP, Bcl-2 via NF-κB pathway. OA also significantly alleviated CDDP-induced hepatotoxicity as evident from the decreased alanine transaminase, aspartate transaminase levels and histochemical evaluation. The possible mechanism may be related to the Nrf-2 induction via its antioxidant mechanism to maintain the redox balance and reduction in CYP2E1 activity which can lead to ROS-mediated oxidative stress. Conclusion: These results suggest that CDDP/OA-LCC NPs have promising applications for co-delivering CDDP and OA to synergize their anti-tumor activity against HCC and to utilize OA’s protective effect against CDDP-induced hepatotoxicity.

Synergism of cisplatin-oleanolic acid co-loaded hybrid nanoparticles on gastric carcinoma cells for enhanced apoptosis and reversed multidrug resistance

“…The content of OA was measured by high-performance liquid chromatography (LC-2030, Shimadzu, Japan) with the following conditions: Agilent SB-C18 880975-902 column (4.6 mm, 250 mm, 5 mm); mobile phase was 0.1% TFA aqueous solution: acetonitrile/methanol mixture (17:1) ¼1:9. The temperature is 30 C, the flow rate was 1 mL/min and the detection wavelength was 210 nm (Khan et al, 2019).…”

Antioxidant Supplementation in the Treatment of Neurotoxicity Induced by Platinum-Based Chemotherapeutics—A Review

“…Hepatotoxicity is also considered as one of the most frequent adverse effects of platinum-based compounds administration in clinical practice. Morphological alterations accompanying platinum-based compounds application are manifested as necrosis, degeneration of hepatocytes, and increased inflammatory response [ 19 ], as well as a consequent increase in hepatic enzymes and bilirubin [ 20 ]. Long-term survival analysis of platinum-based compounds-induced hepatotoxicity showed that liver damage was more pronounced following cisplatin administration when compared to carboplatin [ 21 ], while drug-induced hepatotoxicity manifestations accompanying oxaliplatin therapy were predominantly restricted to hepatic vascular injury [ 22 ].…”

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

“…However, considering the side effects and resistance of antineoplastic drugs of HCC treatment, some new extracts from common plants can directly antagonize HCC growth, improve the anticancer activity, and reduce hepatotoxicity by enhancing p53 function and disrupting MDM2-p53 interaction. Oleanolic acid can help cisplatin to overcome the chemotherapeutic resistance by activating p53/Bax/ cytochrome C/caspase-3 proapoptotic signaling pathway 155 . Acetylshikonin can directly promote HepG2 cell apoptosis by activating p53/PUMA/Bax pathway 156 .…”