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Inhibition of gastric cancer by camptothecin involves apoptosis and multiple cellular pathways
D A Litvak1, H T Papaconstantinou, K O Hwang
1Department of Surgery, University of Texas Medical Branch, Galveston 77555-0533, USA.
Background:
The prognosis for gastric cancer remains dismal; novel agents that target specific molecular pathways are needed as adjuvant therapy. Camptothecin (CPT), on inhibitor of topoisomerase I, is effective in the treatment of certain solid tumors; its effects on gastric cancer are largely undefined. The purpose of this study was to (1) characterize the effects of CPT on the growth of a human gastric cancer and (2) assess potential cellular mechanisms responsible for CPT-mediated growth inhibition.
Methods:
The human gastric cancer SIIA was transplanted subcutaneously into athymic nude mice. After tumors reached approximately 100 mm2, mice were randomized into 3 groups to receive either CPT (5 or 10 mg/kg) or vehicle (control) intraperitoneally 3 days per week for 3 weeks; tumor size was measured biweekly. To assess potential mechanisms of CPT-mediated inhibition, SIIA cells were treated with CPT (20 mumol/L) and cells were counted over a time course; apoptosis was assessed by Hoechst stain and DNA laddering. Expression of p53 (a tumor suppressor), p21Waf1 and p27Kip1 (cell cycle inhibitors), and Bcl-2 and Bcl-XL (antiapoptotic proteins) was determined.
Results:
CPT (5 and 10 mg/kg) significantly inhibited tumor growth of SIIA gastric cancers compared with controls. CPT-mediated inhibition of SIIA cell proliferation was associated with an increase in apoptosis. Moreover, CPT treatment resulted in induction of p53, p21Waf1, and p27Kip1 and a decrease in Bcl-2 and Bcl-XL RNA and protein levels.
Conclusions:
Treatment with CPT effectively inhibited the growth of the human gastric cancer SIIA; the mechanism involved was induction of apoptosis mediated by up-regulation of p53, p21Waf1/Cip1, and p27Kip1 and the down-regulation of Bcl-2 and Bcl-XL. Novel agents such as CPT, which target specific molecular pathways, may prove clinically useful in the adjuvant treatment of gastric cancers.
Insights
Camptothecin (CPT) significantly inhibited human gastric cancer growth in mice by inducing apoptosis. This topoisomerase I inhibitor up-regulated tumor suppressors and cell cycle inhibitors while down-regulating antiapoptotic proteins.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastric cancer has a poor prognosis, necessitating novel adjuvant therapies targeting specific molecular pathways.
- Camptothecin (CPT), a topoisomerase I inhibitor, shows efficacy in solid tumors, but its role in gastric cancer is not well-defined.
Purpose of the Study:
- To characterize the effects of CPT on human gastric cancer SIIA growth.
- To investigate the cellular mechanisms underlying CPT-mediated growth inhibition in gastric cancer.
Main Methods:
- Subcutaneous transplantation of human gastric cancer SIIA into athymic nude mice, followed by CPT or vehicle treatment.
- In vitro assessment of CPT effects on SIIA cell proliferation, apoptosis (Hoechst stain, DNA laddering), and expression of key proteins (p53, p21Waf1, p27Kip1, Bcl-2, Bcl-XL).
Main Results:
- CPT treatment significantly inhibited gastric cancer tumor growth in vivo.
- CPT induced apoptosis and inhibited proliferation of SIIA cells.
- CPT up-regulated p53, p21Waf1, and p27Kip1, while down-regulating Bcl-2 and Bcl-XL expression.
Conclusions:
- CPT effectively inhibits gastric cancer growth by inducing apoptosis through modulation of p53, cell cycle inhibitors, and apoptosis-related proteins.
- CPT represents a potential novel adjuvant therapeutic agent for gastric cancer, targeting specific molecular pathways.