Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity
Muhammad Waseem Khan,1 Pengxuan Zhao,1 Asifullah Khan,2 Faisal Raza,2 Shahid Masood Raza,1 Muhammad Sarfraz,3 Yan Chen,1 Minsi Li,1 Tan Yang,1 Xiang Ma,1 Guangya Xiang11School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People’s...
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Dove Medical Press
2019
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Combination therapy Cisplatin Oleanolic acid Hepatocellular carcinoma Hepatotoxicity. Medicine (General) R5-920 |
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Combination therapy Cisplatin Oleanolic acid Hepatocellular carcinoma Hepatotoxicity. Medicine (General) R5-920 Khan MW Zhao P Khan A Raza F Raza SM Sarfraz M Chen Y Li M Yang T Ma X Xiang G Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
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Muhammad Waseem Khan,1 Pengxuan Zhao,1 Asifullah Khan,2 Faisal Raza,2 Shahid Masood Raza,1 Muhammad Sarfraz,3 Yan Chen,1 Minsi Li,1 Tan Yang,1 Xiang Ma,1 Guangya Xiang11School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People’s Republic of China; 2State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 3School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475001/475004, People’s Republic of ChinaBackground: 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.Keywords: combination therapy, cisplatin, oleanolic acid, hepatocellular carcinoma, hepatotoxicity |
| format |
article |
| author |
Khan MW Zhao P Khan A Raza F Raza SM Sarfraz M Chen Y Li M Yang T Ma X Xiang G |
| author_facet |
Khan MW Zhao P Khan A Raza F Raza SM Sarfraz M Chen Y Li M Yang T Ma X Xiang G |
| author_sort |
Khan MW |
| title |
Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
| title_short |
Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
| title_full |
Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
| title_fullStr |
Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
| title_full_unstemmed |
Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
| title_sort |
synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity |
| publisher |
Dove Medical Press |
| publishDate |
2019 |
| url |
https://doaj.org/article/e7f5d21274f24aa581104e645a301a1b |
| work_keys_str_mv |
AT khanmw synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT zhaop synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT khana synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT razaf synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT razasm synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT sarfrazm synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT cheny synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT lim synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT yangt synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT max synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity AT xiangg synergismofcisplatinoleanolicacidcoloadedcalciumcarbonatenanoparticlesonhepatocellularcarcinomacellsforenhancedapoptosisandreducedhepatotoxicity |
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oai:doaj.org-article:e7f5d21274f24aa581104e645a301a1b2021-12-02T07:32:59ZSynergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity1178-2013https://doaj.org/article/e7f5d21274f24aa581104e645a301a1b2019-05-01T00:00:00Zhttps://www.dovepress.com/synergism-of-cisplatin-oleanolic-acid-co-loaded-calcium-carbonate-nano-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Muhammad Waseem Khan,1 Pengxuan Zhao,1 Asifullah Khan,2 Faisal Raza,2 Shahid Masood Raza,1 Muhammad Sarfraz,3 Yan Chen,1 Minsi Li,1 Tan Yang,1 Xiang Ma,1 Guangya Xiang11School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People’s Republic of China; 2State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 3School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475001/475004, People’s Republic of ChinaBackground: 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.Keywords: combination therapy, cisplatin, oleanolic acid, hepatocellular carcinoma, hepatotoxicityKhan MWZhao PKhan ARaza FRaza SMSarfraz MChen YLi MYang TMa XXiang GDove Medical PressarticleCombination therapyCisplatinOleanolic acidHepatocellular carcinomaHepatotoxicity.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 3753-3771 (2019) |