Combination of novel DR5 targeting agonistic scFv antibody TR2-3 with cisplatin shows enhanced synergistic antitumor activity in vitro and in vivo.
Biomed Pharmacother
; 98: 271-279, 2018 Feb.
Article
em En
| MEDLINE
| ID: mdl-29272788
ABSTRACT
OBJECTIVES:
To investigate the antitumor activity of a novel agonistic single chain fragment variable (scFv) antibody TR2-3 targeting death receptor 5 (DR5) combined with cisplatin in vitro and in vivo.METHODS:
The in vitro cytotoxic effects of TR2-3 and cisplatin, alone or in combination on human cancer cell lines COLO205 and MDA-MB-231 were evaluated using the MTT assay. The apoptosis in cancer cells was evaluated by an Annexin V-PE apoptosis detection kit and flow cytometry. The mRNA and protein levels of DR5 were analyzed by real-time PCR and Western blot, respectively. Additionally, the in vivo antitumor activity of TR2-3 combined with cisplatin was evaluated in a xenograft model.RESULTS:
The combination treatment with TR2-3 and cisplatin for 24â¯h on COLO205 and MDA-MB-231 cells showed significant cytotoxicity effects by MTT assay, compared with the alone treatment. Consistent with cell viability results, the cisplatin enhanced the apoptosis-inducing effects of TR2-3 in the COLO205 cells and MDA-MB-231 cells by flow cytometry. In addition, treatment with cisplatin alone for 24â¯h resulted in significantly up-regulating the mRNA and protein levels of DR5 in both COLO205 and MDA-MB-231 cell lines by q-PCR and Western blot assay. Moreover, the cytotoxic effects of TR2-3 can be blocked by adding the soluble DR5, and the blocking rate can be greatly reduced by co-treatment with cisplatin. These results indicated that cisplatin sensitized COLO205 and MDA-MB-231 cancer cells to TR2-3-mediated apoptosis by up-regulation of DR5 expression. Furthermore, combination therapy with TR2-3 and cisplatin enhanced tumor growth inhibition compared to treatment with TR2-3 or cisplatin alone in mice bearing COLO205 xenograft tumors.CONCLUSIONS:
Our findings suggest that cisplatin enhanced the antitumor activity of TR2-3 in COLO205 and MDA-MB-231 cancer cells through up-regulation of DR5 expression. The TR2-3 combined with cisplatin may be a promising treatment for cancer therapy.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Cisplatino
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Sistemas de Liberação de Medicamentos
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Receptores do Ligante Indutor de Apoptose Relacionado a TNF
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Anticorpos de Cadeia Única
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Antineoplásicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article