Liposomal co-delivered oleanolic acid attenuates doxorubicin-induced multi-organ toxicity in hepatocellular carcinoma
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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
Guangya Xiang, email: email@example.com
Xiang Ma, email: firstname.lastname@example.org
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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