STRAIL-iRGD is a promising therapeutic agent for gastric cancer treatment

Ying Huang,Xihan Li,Xinyu Bian,Xiao Han,Lianru Zhang,Huizi Sha,Baorui Liu

doi:10.1038/s41598-017-00688-6

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells and augments chemotherapeutics in vivo. Here, we developed sTRAIL-iRGD, a recombinant protein consisting of sTRAIL fused to CRGDKGPDC, a C-terminal end binding peptide with an integrin-binding arginine-glycine-aspartic acid (iRGD) motif. CRGDKGPDC is a tumor-homing peptide with high penetration into tumor tissue and cells. We found that sTRAIL-iRGD internalized into cultured gastric cancer tumor cells and localized to both the tumor mass in vivo and three-dimensional multicellular spheroids in vitro. sTRAIL-iRGD had an antitumor effect in tumor cell lines, multicellular spheroids and nude mice with tumors. Repeated treatment with sTRAIL-iRGD reduced tumor growth and volume in vivo. Mice treated with sTRAIL-iRGD and paclitaxel (PTX) in combination showed no sign of sTRAIL-iRGD-related liver toxicity. Our data suggest that sTRAIL-iRGD is a promising anti-gastric cancer agent with high selectivity and limited systemic toxicity.

Highlights

Despite recent progress in cancer immune therapy, radiotherapy and chemotherapy, gastric cancer continues to have high mortality rates globally, especially in the Eastern world[1,2,3]
After IPTG induction, three protein bands appeared at 20 kDa and 22 kDa in coomassie blue-stained sodium dodecyl sulfate (SDS)-PAGE
These results validated the successful production of soluble sTRAIL and sTRAIL-integrin-binding arginine-glycine-aspartic acid (iRGD)

Summary

Introduction

Despite recent progress in cancer immune therapy, radiotherapy and chemotherapy, gastric cancer continues to have high mortality rates globally, especially in the Eastern world[1,2,3]. STRAIL, a soluble form of TRAIL, can be proteolytically cleaved, and can maintain its original tumor cell killing activity . 3D MCS culture conditions generate an extracellular matrix (ECM) that obstructs drug penetration into tumor tissues[15, 16]. We undertook this study using 3D MCS with gastric cancer cells to elucidate sTRAIL antitumor activities and explore sTRAIL as an antitumor drug. To circumvent the issue of low drug penetration into solid tumors and to efficiently deliver sTRAIL into the tumor, we fused CRGDKGPDC, a C-terminal end binding peptide with an integrin-binding arginine-glycine-aspartic acid (iRGD) motif, to sTRAIL. CRGDKGPDC is proteolytically cleaved to CRGDK/R, which binds and activates the receptor Neuropilin-1 (NRP-1), as a transmembrane protein, involves in mediating the peptide’s penetration into tissues[21]. We examined sTRAIL-iRGD anticancer activity in combination with paclitaxel (PTX) in vitro, using the 3D MCS model, and in vivo

Methods

Results

Conclusion