Novel oncolytic adenovirus selectively targets tumor-associated polo-like kinase 1 and tumor cell viability.
OBJECTIVE
Polo-like kinase 1 (plk1) is a serine/threonine protein kinase essential for multiple mitotic processes. Previous observations have validated plk1 as a promising therapeutic target. Despite being conceptually attractive, the potency and specificity of current plk1-based therapies remain limited. We sought to develop a novel plk1-targeting strategy by constructing an oncolytic adenovirus to selectively silence plk1 in tumor cells.


METHODS
Two artificial features were engineered into one wild-type adenovirus type 5 (wt-Adv5) genome to generate a new oncolytic adenovirus (M1). First, M1 contains a 27-bp deletion in E1A region, which confers potent, oncolytic efficacy. Second, M1 is armed with a fragment of antisense plk1 cDNA that substitutes the E3 region encoding 6.7K and gp19K. In this design, tumor-selective replication of M1 would activate the native adenovirus E3 promoters to express the antisense plk1 cDNA preferentially in tumor cells and silence tumor-associated plk1 protein.


RESULTS
By virtue of combining oncolysis with plk1 targeting, M1 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M1 plus cisplatin induced complete tumor regression in 80% of orthotopic hepatic carcinoma model mice that were otherwise resistant to cisplatin and disseminated metastases.


CONCLUSIONS
Coupling plk1 targeting with oncolysis had shown superior antitumor efficacy. Present findings would benefit the development of novel oncolytic adenoviruses generally applicable to a wide range of molecule-based therapeutics.
Zhou
Jianfeng
J
Cancer Biology Research Center, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, WuHan, Hubei, PR China.
Gao
Qinglei
Q
Chen
Gang
G
Huang
Xiaoyuan
X
Lu
Yunping
Y
Li
Kanyan
K
Xie
Daxing
D
Zhuang
Liang
L
Deng
Jingniu
J
Ma
Ding
D
D000256:Adenoviridae / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000172:deficiency* / Q000235:genetics; D017503:Adenovirus E3 Proteins / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use; D003588:Cytopathogenic Effect, Viral / Q000502:physiology*; D016373:DNA, Antisense / Q000235:genetics; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
D017500:Adenovirus E1A Proteins; D017503:Adenovirus E3 Proteins; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002945:Cisplatin; D016373:DNA, Antisense; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1