Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide [1]
Oleanolic acid (OA) was less active than DOX (Figure 1B)
We investigated co-delivery of OA and chemotherapeutics as a potential therapeutic strategy for hepatocellular carcinoma (HCC)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide [1]. Single-agent chemotherapy is not sufficient to prevent reoccurrence because of tumor heterogeneity and the complexity of cell signaling pathways. Targeted and combination therapies are frequently used to treat HCC and many regimens have been investigated in clinical trials [2]. Chemotherapeutics in combination with natural compounds is an attractive approach for HCC treatment [5]. The anthracycline anticancer drug doxorubicin (DOX) is effective for various malignancies but it can cause cardiotoxicity. The mechanisms underlying DOX-induced cardiotoxicity are distinct from those responsible for the therapeutic effects [6]. Cardiotoxicity is caused by increased oxidative stress and free radical formation (reactive oxygen species, ROS) [7,8,9,10]. DOX-induced 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE) production [11] promotes cardiomyocyte apoptosis through the intrinsic (mitochondrial) pathway, which can damage the heart [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
