Article

Antitumor effect of axitinib combined with dopamine and PKPD modeling in the treatment of human breast cancer xenograft

Authors: Yuan-heng Ma1,2, Si-yuan Wang1,2, Yu-peng Ren1, Jian Li1, Ting-jie Guo1, Wei Lu1, Tian-yan Zhou1
1 Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2 Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Correspondence to: Tian-yan Zhou: tianyanzhou@bjmu.edu.cn,
DOI: 10.1038/s41401-018-0006-x
Received: 18 October 2017
Accepted: 20 January 2018
Advance online: 17 May 2018

Abstract

Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX’s efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44+/CD24−/low) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.
Keywords: Cancer stem-like cell; Dopamine; Axitinib; Combination therapy; Pharmacokinetic-pharmacodynamic model

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