A bispecific fusion protein and a bifunctional enediyne-energized fusion protein consisting of TRAIL, EGFR peptide ligand, and apoprotein of lidamycin against EGFR and DR4/5 show potent antitumor activity. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Zhu, Daqiang; Wang, Xiaofei; Shang, Yue; Li, Yi; Jiang, Wenguo; Li, Liang; Chen, Shu-zhen
• Is Part Of: Anti-cancer drugs. Volume 26:Issue 1(2015)
• Publication Date: 2015-01
• Subjects: death receptor 4 -- death receptor 5 -- epidermal growth factor receptor -- lidamycin -- TRAIL; Antineoplastic agents -- Periodicals; Cancer -- Chemotherapy -- Periodicals; Antineoplastic Agents -- therapeutic use -- Periodicals; Drug Therapy -- Periodicals; 616.994061
• DOI: 10.1097/CAD.0000000000000160
• Languages: English
• ISSNs: 0959-4973

Abstract

Abstract : Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mainly induces apoptosis through the extrinsic death receptor-induced pathway by ligation with death receptor 4 (DR4) and death receptor 5 (DR5). On the basis of the antitumor activity to cancer cells and no cytotoxity to normal cells of TRAIL and the target of the epidermal growth factor receptor (EGFR) ligand peptide, the study constructed a new bispecific fusion protein and a new bifunctional enediyne-energized fusion protein and investigated their antitumor efficacy. Bispecific fusion protein Ec-LDP-TRAIL showed potent binding activity to cancer cell lines with a high expression of EGFR or DR4/DR5 such as A431 and H460 cells, whereas poor binding activity to NIH/3T3 cells with low expressing EGFR and DR4/DR5. Ec-LDP-TRAIL also showed more potent cytotoxicity to A431 and H460 cells than Ec-LDP, which could result from the TRAIL-inducing apoptosis. Results of an in-vivo efficacy study showed that Ec-LDP-TRAIL at a dose of 10 mg/kg decreased the growth of epidermoid carcinoma A431 xenografts by 80.19% ( P <0.01) on day 26. Immunohistochemical detection of nuclear antigen factor Ki-67 suggested that Ec-LDP-TRAIL effectively induced cell necrosis and inhibited cell proliferation of tumor. From IC50 values, bispecific and bifunctional energized fusion protein Ec-LDP-TRAIL-AE was more potent and selective in its cytotoxicity against different carcinoma cell lines than corresponding lidamycin in vitro and induction of the cleavage of poly(ADP-ribose)polymerase was observed in A431 cells treated with Ec-LDP-TRAIL-AE and lidamycin, respectively. Ec-LDP-TRAIL-AE also significantly inhibited the growth of A431 xenografts in a nude mouse model. These properties suggested that Ec-LDP-TRAIL and Ec-LDP-TRAIL-AE may be promising candidates for targeted cancer therapy. Abstract : Supplemental Digital Content is available in the text.