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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
The small molecule survivin inhibitor YM155 may be an effective treatment modality for colon cancer through
Wan Lu Li1, Mi-Ra Lee1, Mee-Yon Cho2
1Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, South Korea.
Abstract:
Survivin has a known beneficial role in the survival of both cancer cells and normal cells. Therapies targeting survivin have been proposed as an alternative treatment modality for various tumors; however, finding the proper indication for this toxic therapy is critical for reducing unavoidable side effects. We recently observed that high survivin expression in CD133(+) cells is related to chemoresistance in Caco-2 colon cancer cells. However, the effect of survivin-targeted therapy on CD133(+) colon cancer is unknown. In this study, we investigated the roles of CD133 and survivin expression in colon cancer biology in vitro and comparatively analyzed the anticancer effects of survivin inhibitor on CD133(+) cells (ctrl-siRNA group) and small interfering RNA (siRNA)-induced CD133(-) cells (CD133-siRNA group) obtained from a single colon cancer cell line. CD133 knockdown via siRNA transfection did not change the tumorigenicity of cells, although in vitro survivin expression levels in CD133(+) cells were higher than those in siRNA-induced CD133(-) cells. The transfection procedure seemed to induce survivin expression. Notably, a significant number of CD133(-) cells (33.8%) was found in the cell colonies of the CD133-siRNA group. In the cell proliferation assay after treatment, YM155 and a combination of YM155 and 5-fluorouracil (5-FU) proved to be far more effective than 5-FU alone. A significantly increased level of apoptosis was observed with increasing doses of YM155 in all groups. However, significant differences in therapeutic effect and apoptosis among the mock, ctrl-siRNA, and CD133-siRNA groups were not detected. Survivin inhibitor is an effective treatment modality for colon cancer; however, the role of CD133 and the use of survivin expression as a biomarker for this targeted therapy must be verified.
Insights
Survivin inhibitor YM155 effectively treats colon cancer, inducing apoptosis. However, the role of CD133 expression in predicting treatment response requires further investigation to optimize this targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Survivin promotes survival in cancer and normal cells, making it a target for cancer therapies.
- High survivin expression in CD133-positive cells correlates with chemoresistance in colon cancer.
- The therapeutic impact of survivin-targeted therapy on CD133-positive colon cancer remains unclear.
Purpose of the Study:
- To investigate the roles of CD133 and survivin in colon cancer biology.
- To compare the efficacy of survivin inhibition in CD133-positive versus CD133-negative colon cancer cells.
- To evaluate survivin inhibitor YM155, alone and in combination with 5-fluorouracil, for colon cancer treatment.
Main Methods:
- Utilized siRNA to knockdown CD133 expression in a colon cancer cell line.
- Assessed cell proliferation and apoptosis following treatment with YM155 and 5-fluorouracil.
- Analyzed survivin and CD133 expression levels in vitro.
- Compared therapeutic effects and apoptosis rates across different cell groups.
Main Results:
- CD133 knockdown did not alter cell tumorigenicity, but survivin expression was higher in CD133-positive cells.
- YM155 and YM155/5-FU combination therapy were more effective than 5-FU alone in cell proliferation assays.
- Increased YM155 dosage significantly elevated apoptosis levels across all groups.
- No significant differences in therapeutic effect or apoptosis were observed between mock, control-siRNA, and CD133-siRNA groups.
Conclusions:
- Survivin inhibitor YM155 demonstrates efficacy as a colon cancer treatment modality.
- The role of CD133 as a predictive biomarker for survivin-targeted therapy needs further validation.
- Optimizing survivin-targeted therapies requires a clearer understanding of CD133's influence and survivin's biomarker utility.
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