Research Papers:

Liposomal co-delivered oleanolic acid attenuates doxorubicin-induced multi-organ toxicity in hepatocellular carcinoma

Muhammad Sarfraz, Attia Afzal, Shahid Masood Raza, Sajid Bashir, Asadullah Madni, Muhammad Waseem Khan, Xiang Ma and Guangya Xiang _

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Oncotarget. 2017; 8:47136-47153. https://doi.org/10.18632/oncotarget.17559

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Muhammad Sarfraz1,2,*, Attia Afzal1,3,*, Shahid Masood Raza1, Sajid Bashir2, Asadullah Madni4, Muhammad Waseem Khan1, Xiang Ma1 and Guangya Xiang1

1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

2Department of Pharmacy, University of Sargodha, Sargodha, 40100, Punjab, Pakistan

3Institute of Pharmacy, Lahore College for Women University, Lahore, 54610, Punjab, Pakistan

4Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Bahawalpur, 63100, Punjab, Pakistan

*These authors contributed equally to this work

Correspondence to:

Guangya Xiang, email: gyxiang1968@hotmail.com

Xiang Ma, email: xiangma@hust.edu.cn

Keywords: oleanolic acid, doxorubicin, cardiotoxicity, 20-HETE, HCC

Received: January 17, 2017     Accepted: April 18, 2017     Published: May 02, 2017


Doxorubicin in combination with other cytotoxic drugs has clinical advantages. However, doxorubicin-induced cardiotoxicity negatively impacts clinical utility and outcomes. Cardiotoxicity can result from increased oxidative stress or from a local cytochrome P450 mediated increase in 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE). Oleanolic acid (OA) is a natural pentacyclic triterpenoid with free radical scavenging, cardioprotective, and P450-mediated cyclooxygenase-upregulating properties. We investigated co-delivery of liposomal OA and doxorubicin in a HepG2 model of hepatocellular carcinoma (HCC). OA attenuated the cardiotoxicity induced by doxorubicin without compromising its anticancer activity. Apoptosis assays revealed that co-delivery of DOX and OA produced a synergistic anticancer effect. However, the drugs had antagonistic effects on cardiomyocytes. Female BALB/c nude mice treated with OA- and DOX-loaded liposomes (ODLs) exhibited reduced tumor growth, stable body weight, and stable organ indices. Reduced 20-HETE production suggested ODLs had limited cardiotoxicity. No changes in biochemical or histopathological markers were observed in mice treated with ODLs. Tailored co-delivery of OA and DOX may thus be an effective therapeutic strategy for treating HCC.

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