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CPT21, a novel compound with anti-proliferative effect against gastric cancer cell SGC7901
Bo Zhang1, Yu Luo, Qinjie Weng
1College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Abstract:
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.
Insights
7-[(3-piperidyl)-1-propinyl]-camptothecin (CPT21), a novel camptothecin analogue, exhibits broad anti-tumor activity in vitro and in vivo. CPT21 induces cancer cell apoptosis by disrupting DNA topoisomerase I and activating caspase cascades.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Camptothecin analogues are crucial in cancer therapy.
- Novel semi-synthetic water-soluble camptothecin analogue CPT21 was developed.
- Understanding CPT21's anti-tumor mechanisms is essential.
Purpose of the Study:
- To evaluate the anti-tumor efficacy of CPT21 in vitro and in vivo.
- To elucidate the molecular mechanisms underlying CPT21's anti-cancer effects.
- To assess CPT21's impact on DNA topoisomerase I and apoptosis.
Main Methods:
- In vitro anti-tumor screening against ten cancer cell lines.
- Assessment of DNA topoisomerase I inhibition and DNA double-strand breaks.
- Flow cytometry analysis of apoptosis and mitochondrial membrane potential.
- Western blot analysis of key apoptosis-related proteins.
- In vivo efficacy study using SGC7901 xenograft mouse model.
Main Results:
- CPT21 demonstrated a broad anti-tumor spectrum with IC50 values from 0.1 to 12.0 microM.
- CPT21 inhibited DNA topoisomerase I, induced DNA double-strand breaks, and triggered apoptosis in SGC7901 cells.
- CPT21 modulated apoptosis-related proteins including p53, BAX, Bcl-2, and caspase-9.
- Significant tumor inhibition rates of 42.5% and 75.1% were observed with 5.0 mg/kg and 10.0 mg/kg CPT21, respectively.
Conclusions:
- CPT21 exhibits potent and broad-spectrum anti-tumor activity.
- CPT21 induces cancer cell apoptosis through caspase cascade activation and mitochondrial dysfunction.
- CPT21 represents a promising therapeutic agent for various cancers.
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