Trastuzumab Induced Chemobrain, Atorvastatin Rescued Chemobrain with Enhanced Anticancer Effect and without Hair Loss-Side Effect.

Seonhwa Lee,Young-Cheol Lim,Hae-June Lee,Eun-Ho Kim,Sang Moo Lim,Jung Min Kim,Yong Jin Lee,Hyunji Kang,Hyejin Park,Jin Su Kim

doi:10.3390/jcm8020234

Abstract

The authors identified that chemo-brain was induced after trastuzumab (TZB) therapy. In addition, atorvastatin (ATV) could rescue chemo-brain during trastuzumab (TZB) therapy. Enhanced therapeutic effect of TZB was confirmed after ATV therapy. We also investigated that there was no hair loss side effect due to ATV therapy. In an animal model, 150 μg TZB and five serial doses of 20 mg/kg ATV were administered. 18F-fluorodeoxyglucose Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) data were acquired. Statistical parametric mapping analysis and voxel-based morphometry analysis were performed to identify differences in glucose metabolism and gray matter concentration. The enhanced therapeutic efficacy of TZB after ATV treatment was assessed using a human epidermal growth factor receptor 2-positive gastric cancer model. We found a decrease in cerebral glucose metabolism and gray matter concentration in the frontal lobe following TZB therapy (p < 0.005). After subsequent ATV administration, glucose metabolism and regional gray matter concentration were rescued (p < 0.005). Cognitive impairment due to TZB and the rescue effect of ATV were confirmed using a passive avoidance test and quantitative real-time reverse transcription PCR. Furthermore, the penetration and accumulation of TZB in tumors increased by 100% after ATV co-administration, which resulted in an enhanced anti-cancer effect. Our study collectively demonstrates that ATV co-administration with TZB rescued the TZB-induced chemo-brain and enhances the therapeutic efficacy of TZB in tumors. We also showed that there was no hair loss during ATV therapy.

Highlights

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor involved in the pathogenesis of several cancers, including advanced gastric and gastroesophageal junction cancer [1].HER2 protein binds to an extracellular ligand binding domain that initiates a signal transduction cascade that affects tumor cell biology through several mechanisms, including cell proliferation, apoptosis, adhesion, migration, and differentiation [2]
A decrease in cerebral glucose metabolism was observed in the region of the bilateral frontal lobe after administration of TZB or CTX compared with the baseline level (Figure 1B,C, p < 0.005)
There was a decrease in gray matter concentration in the region of the frontal association cortex on the left side following TZB therapy, and in the region of the frontal association cortex and hippocampus on the left side following CTX therapy, relative to baseline (Figure 2B,C, p < 0.005)

Summary

Introduction

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor involved in the pathogenesis of several cancers, including advanced gastric and gastroesophageal junction cancer [1]. HER2 protein binds to an extracellular ligand binding domain that initiates a signal transduction cascade that affects tumor cell biology through several mechanisms, including cell proliferation, apoptosis, adhesion, migration, and differentiation [2]. Trastuzumab (TZB) (Roche, Boston, MA, USA) is the first humanized monoclonal antibody (mAb) approved for immunotherapy and the first oncogene-targeted treatment with a proven survival benefit in HER2-positive cancer [3]. Several studies have examined the efficacy of anti-HER2 therapies in both in vitro and in vivo models of gastric cancer using TZB and have shown that TZB leads to decreased HER2 signaling and inhibits cell growth [4]. There was no report regarding chemo-brain after TZB therapy

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Conclusion