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Selective activity of BS-RNase against anaplastic thyroid cancer
R Kotchetkov1, J Cinatl, A A Krivtchik
1Pediatric Clinic for Hematology and Oncology, University Clinics, Johann Wolfgang Goethe-University, Paul-Ehrlich Str. 40, D-60596 Frankfurt am Main, Germany.
Background:
Anaplastic thyroid carcinoma is an aggressive solid tumor that fails to adequately respond to any known chemotherapeutic regimen. The development of effective chemotherapy agents would provide the best chance for long-term survival of patients.
Materials And Methods:
The cytotoxic effects of bovine seminal ribonuclease (BS-RNase) against thyroid carcinoma cell lines with different degrees of differentiation in comparison to non-malignant cells, including human foreskin fibroblasts (HFF) and retinal pigment epithelial cells (RPE), were tested using the MTT dye reduction assay. Induction of apoptosis was demonstrated by annexin V assay and expression of proteins related to apoptosis was investigated by flow cytometry. The antitumoral in vivo effects of BS-RNase were assessed on established xenografts of anaplastic thyroid carcinoma cell line 8505C in nude mice using subcutaneous injections of BS-RNase (12.5 mg/kg once a day, on 20 consecutive days).
Results:
All the tumor cell lines exhibited marked sensitivity against BS-RNase in comparison to HFF and RPE cells. The greatest growth inhibition was seen in the 8505C line, while IC50 values for papillary (B-CPAP) and poorly-differentiated thyroid carcinoma cells were about 6-fold higher. The cytotoxic action of BS-RNase was associated with induction of apoptosis. Expressions of Fas and Fas-ligand were not influenced by BS-RNase completely, while the down-regulation of Bcl-2 in treated cells was observed. In vivo treatment induced significant tumor regression after the course of 20 consecutive days. No apparent toxic effects of BS-RNase toward non-malignant cells were observed during the in vivo treatment. After cessation of therapy (day 20) tumor volume continued to decrease and the tumor was no longer detectable after 30 days of treatment induction in all animals.
Conclusion:
BS-RNase may have beneficial effects for treatment of aggressive anaplastic thyroid cancer.
Insights
Bovine seminal ribonuclease (BS-RNase) shows potent anti-cancer effects against aggressive anaplastic thyroid cancer cells. This enzyme effectively reduced tumor size in vivo without apparent toxicity, offering a promising new therapeutic avenue.
Area of Science:
- Biochemistry
- Oncology
- Enzymology
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with limited treatment options.
- Current chemotherapeutic regimens are largely ineffective against ATC.
- Development of novel chemotherapy agents is crucial for improving patient survival.
Purpose of the Study:
- To investigate the cytotoxic effects of bovine seminal ribonuclease (BS-RNase) on various thyroid carcinoma cell lines.
- To evaluate the potential of BS-RNase as a therapeutic agent for anaplastic thyroid cancer.
Main Methods:
- Cytotoxicity was assessed using the MTT assay on differentiated and undifferentiated thyroid carcinoma cell lines and non-malignant cells (HFF, RPE).
- Apoptosis induction was confirmed via annexin V assay and flow cytometry analysis of apoptosis-related proteins.
- In vivo efficacy was evaluated using BS-RNase in a xenograft model of ATC (8505C cell line) in nude mice.
Main Results:
- BS-RNase demonstrated significant cytotoxicity against all tested thyroid carcinoma cell lines compared to non-malignant cells.
- The 8505C cell line showed the highest sensitivity to BS-RNase.
- In vivo administration of BS-RNase led to significant tumor regression and complete tumor disappearance in all animals within 30 days, with no observed toxicity.
Conclusions:
- BS-RNase exhibits potent anti-tumor activity against anaplastic thyroid cancer.
- The mechanism involves the induction of apoptosis and down-regulation of Bcl-2.
- BS-RNase represents a promising therapeutic candidate for aggressive anaplastic thyroid cancer.