Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205.
CPT-11 (irinotecan) is a derivative of camptothecin which is a natural product derived from the Chinese tree Camptotheca acuminta and widely used in antitumor therapy. Here, the in vitro anti-tumor activity and associated mechanisms of a novel derivative of camptothecin, ZBH-1205, were investigated in a panel of 9 human tumor cell lines, as well as in HEK 293 and SK-OV-3/DPP, a multi-drug resistant (MDR) cell line, and compared to CPT-11 and 7-ethyl-10-hydroxy-camptothecin (SN38). Comparisons between the different compounds were made on the basis of IC50 values as determined by the MTT assay, and flow cytometry was used to evaluate cell cycle progression, apoptosis, and the levels of pro- and active caspase-3 among different treatment groups. Interaction between the molecules and topoisomerase-1 (Topo-1)-DNA complexes was detected by a DNA relaxation assay. Our results demonstrated that IC50 values for ZBH-1205 ranged from 0.0009 μmol/L to 2.5671 μmol/L, which were consistently lower than IC50 values of CPT-11 or SN38 in the panel of cell lines, including SK-OV-3/DPP. Furthermore, ZBH-1205 was more effective than CPT-11 or SN38 at stabilizing Topo-1-DNA complexes and inducing tumor cell apoptosis. Therefore, ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials.
Tumor Center of Jilin University No.1 Hospital, Changchun 130021, China.
Di
D
Wu
Institute of Pharmacology and Toxicology Academy of Military Medical Sciences, Beijing 100850, China.
Weiguo
W
Shi
Key Lab for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, China.
Jing
J
Zhao
Department of Pharmacology, Bethune Medical College, Jilin University, Changchun 130021, China.
Zhengren
Z
Wei
Department of Pharmacology, Bethune Medical College, Jilin University, Changchun 130021, China.
Zhijia
Z
Chen
Jilin Province Tumor Hospital, Changchun 130021, China.
Dawei
D
Zhao
Tumor Center of Jilin University No.1 Hospital, Changchun 130021, China.
Shijie
S
Lan
Tumor Center of Jilin University No.1 Hospital, Changchun 130021, China. Electronic address: jiandongtai@sina.com.
Jiandong
J
Tai
Institute of Pharmacology and Toxicology Academy of Military Medical Sciences, Beijing 100850, China. Electronic address: bohuazhong@yahoo.com.
Bohua
B
Zhong
Cell Biology Laboratory, Jilin Province Tumor Institute, Changchun 130021, China. Electronic address: yhzhlyy@126.com.
Hong
H
Yu
D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D029769:Camptotheca / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D020014:K562 Cells; D007700:Kinetics; D010936:Plant Extracts
D000970:Antineoplastic Agents; D010936:Plant Extracts; C000618348:ZBH-1205; D000077146:Irinotecan; D004247:DNA; C505407:CASP3 protein, human; D053148:Caspase 3; D002166:Camptothecin
Apoptosis; CPT-11; Camptothecin derivatives; SN38; Topoismerase