Enhanced therapeutic efficacy of doxorubicin against multidrug-resistant breast cancer with reduced cardiotoxicity

Abstract

Doxorubicin (DOX), a commonly used anti-cancer drug, is limited by its cardiotoxicity and multidrug resistance (MDR) of tumor cells. Epigallocatechin gallate (EGCG), a natural antioxidant component, can effectively reduce the cardiotoxicity of DOX. Meanwhile, EGCG can inhibit the expression of P-glycoprotein (P-gp) and reverse the MDR of tumor cells. In this study, DOX is connected with low molecular weight polyethyleneimine (PEI) via hydrazone bond to get the pH-sensitive PEI-DOX, which is then combined with EGCG to prevent the cardiotoxicity of DOX and reverse the MDR of cancer cells. In addition, folic acid (FA) modified polyethylene glycol (PEG) (PEG-FA) is added to get the targeted system PEI-DOX/EGCG/FA. The MDR reversal and targeting ability of PEI-DOX/EGCG/FA is performed by cytotoxicity and in vivo anti-tumor activity on multidrug resistant MCF-7 cells (MCF-7/ADR). Additionally, we investigate the anti-drug resistant mechanism by Western Blot. The ability of EGCG to reduce DOX cardiotoxicity is confirmed by cardiotoxicity assay. In conclusion, PEI-DOX/EGCG/FA can inhibit the expression of P-gp and reverse the MDR in tumor cells. It also shows the ability of remove oxygen free radicals effectively to prevent the cardiotoxicity of DOX.

Keywords:

• Cardiotoxicity
• multidrug resistance
• active targeting
• pH-sensitive
• immunogenic cell death (ICD)

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval statement

Male nude mice were provided from the Chengdu Dossy Experimental Animals Co., Ltd (Chengdu, China). All animal procedures were carried out per the Regulations for the Care and Use of Laboratory Animals: Eighth Edition. (Washington, DC: The National Academies Press). All animal experiments were approved by Yantai University Laboratory Animal Ethics Committee, affiliated to Yantai University (Approval number, YTDX 20180124). The ARRIVE criteria were followed in all animal experiments.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.