Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking β1 integrin activation.

Li-Yan Li,Hui-Hui Cao,Wei Zheng,Ze-Peng Du,Li-Yan Xu,Fa-Min Zeng,Lian-Di Liao,En-Min Li,Ying-Li Zhang,Hong Chen,Hong Jiang,Xiu-E Xu,Bo Chen,Wei Jia,Yang-Min Xie,Jian-Jun Xie,Wei Huang

doi:10.18632/oncotarget.3612

Abstract

The paucity of new drugs for the treatment of esophageal squamous cell carcinoma (ESCC) limits the treatment options. This study characterized the therapeutic efficacy and action mechanism of a novel natural macrolide compound F806 in human ESCC xenograft models and cell lines. F806 inhibited growth of ESCC, most importantly, it displayed fewer undesirable side effects on normal tissues in two human ESCC xenograft models. F806 inhibited proliferation of six ESCC cells lines, with the half maximal inhibitory concentration (IC50) ranging from 9.31 to 16.43 μM. Furthermore, F806 induced apoptosis of ESCC cells, contributing to its growth-inhibitory effect. Also, F806 inhibited cell adhesion resulting in anoikis. Mechanistic studies revealed that F806 inhibited the activation of β1 integrin in part by binding to a novel site Arg610 of β1 integrin, suppressed focal adhesion formation, decreased cell adhesion to extracellular matrix and eventually triggered apoptosis. We concluded that F806 would potentially be a well-tolerated anticancer drug by targeting β1 integrin, resulting in anoikis in ESCC cells.

Highlights

Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is one of the most frequent fatal malignancies worldwide and the fourth leading cause of cancer-related death in China [1]
A significant (P < 0.05) antitumor effect of F806 was displayed in EC109 and KYSE510 xenograft models beginning at day 8/9 after the start of treatment
This study reported on the efficacy and mechanism of action of a novel macrolide analog F806 in preclinical models of esophageal squamous cell carcinoma (ESCC)

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is one of the most frequent fatal malignancies worldwide and the fourth leading cause of cancer-related death in China [1]. Eighteen α-subunits and eight β-subunits assemble into 24 different integrins [11] Among these integrins, β1 integrin has recently been shown to play a key role in regulating the switch from a dormant state to active proliferation and metastasis, and confer therapeutic resistance in multiple solid cancer models [12,13,14,15,16]. Β1 integrin has recently been shown to play a key role in regulating the switch from a dormant state to active proliferation and metastasis, and confer therapeutic resistance in multiple solid cancer models [12,13,14,15,16] It has been reported several possible therapeutic approaches, such as small molecules or inhibitory antibodies, directing against β1 integrin signaling to prevent the recurrence of cancer in experimental models [17,18,19]. Β1 integrin as a strategic molecular target of a novel chemotherapeutic agent has not been well investigated in ESCC

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