CPT21, a novel compound with anti-proliferative effect against gastric cancer cell SGC7901.
7-[(3-piperidyl)-1-propinyl]-camptothecin (CPT21) is a novel semi-synthetic water-soluble analogue of camptothecin. In this context, we assessed the anti-tumor activity of CPT21 both in vivo and in vitro and explored its molecular mechanism. We found that CPT21 presented a broad anti-tumor spectrum against ten cancer cell lines in vitro, and the IC(50) values ranged from 0.1 to 12.0 microM. CPT21 was also capable to interrupt the DNA topoisemerase I activity and caused DNA double strand breaks during DNA replication. Proportion of apoptotic SGC7901 cells induced by CPT21 showed a time- and concentration-dependent increase accompanied with the decrease in mitochondria membrane potential (DeltaPsim). We also observed that CPT21 up-regulated the protein expression of p53, phospho-p53, p21, BAX, phospho-c-Jun NH2-terminal protein kinase (JNK), meanwhile down-regulating the protein expression of Bcl-2, procaspase-9, XIAP, and phospho-ERK1/2. In the study of SGC7901 xenograft model, the results suggested that both 5.0 mg/kg and 10.0 mg/kg CPT21 achieved high anti-tumor activity, and the tumor inhibition rates were 42.5% and 75.1% respectively. Taken together, our study demonstrates that CPT21 displays an extensive anti-tumor spectrum and CPT21 can induce the apoptosis of SGC7901 cells via activating the caspases cascade followed by disrupting mitochondrion function.
Zhang
Bo
B
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Luo
Yu
Y
Weng
Qinjie
Q
He
Qiaojun
Q
Lu
Wei
W
Yang
Bo
B
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
C534541:7-((3-piperidyl)-1-propynyl)camptothecin; D000970:Antineoplastic Agents; D020169:Caspases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin