CPT21, a novel compound with anti-proliferative effect against gastric cancer cell SGC7901
- 136 Downloads
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 IC50 values ranged from 0.1 to 12.0 μM. 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 (ΔΨm). 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.
KeywordsCamptothecin Gastric cancer Apoptosis Xenograft
This study receives financial support from Health Bureau of Zhejiang Province Foundation (No.WKJ2006-2-015) and is sponsored by Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.
- 3.Lesueur-Ginot L, Demarquay D, Kiss R, Kasprzyk PG, Dassonneville L, Bailly C, Camara J, Lavergne O, Bigg DC (1999) Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res 59:2939–2943PubMedGoogle Scholar
- 8.Lesueur-Ginot L, Demarquay D, Kiss R, Kasprzyk PG, Dassonneville L, Bailly C, Camara J, Lavergne O, Bigg DC (1999) Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase i-targeted activity and antitumor properties. Cancer Res 59:2939–2943PubMedGoogle Scholar
- 28.Cummins JM, Kohli M, Rago C, Kinzler KW, Vogelstein B, Bunz F (2004) X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells. Cancer Res 64:3006–3008PubMedCrossRefGoogle Scholar