Tumoricidal activity of combining the agonistic DR5 antibody D-6 with cisplatin in C30 cisplatin-resistant ovarian cancer in vitro and in vivo.
A previous study by our group reported that the agonistic DR5 antibody D-6 was capable of triggering apoptosis in A2780 cisplatin-sensitive ovarian cancer cells and that this marked effect was enhanced by cisplatin in vitro. The present study examined whether D-6 and cisplatin may exert the same anti-tumor effect on C30 cisplatin-resistant ovarian cancer cells, and the underlying mechanisms were investigated. D-6 exhibited an apoptosis-inducing effect, increased the cell growth inhibition rate of C30 cells in a dose-dependent manner, induced significant morphological changes characteristic for apoptosis, as observed by electron microscopy, and downregulated the expression of caspase 3, 8 and 9 precursors in C30 cells treated with D-6 at the protein level. All of these effects were evidently enhanced when accompanied by cisplatin. Furthermore, D-6 alone or in combination with cisplatin in the established models of C30 tumor xenografts resulted in a significant repression of tumor growth, and evident apoptosis, as determined by a terminal transferase dUTP nick end labeling assay. In addition, the expression of caspase 3, 8 and 9 precursors in the tumor xenografts was as similar to that found in vitro. In conclusion, the present study suggested that D-6 may serve as a novel anti-tumor agent against C30 cisplatin‑resistant ovarian cancer, with the ability to trigger apoptosis via caspase-dependent and ‑independent pathways and the potential to decrease the cisplatin resistance of the C30 cell line.
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Yan
Y
Huang
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Baoquan
B
Liang
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Qin
Q
Jiang
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Chen
C
Chen
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Kun
K
Yang
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Chunmei
C
Li
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Ai
A
Zheng
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D014183:Transplantation, Heterologous
D000906:Antibodies; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D002945:Cisplatin