Noncanonical functions of telomerase and telomeres in viruses-associated cancer.

The cause of cancer is attributed to the uncontrolled growth and proliferation of cells resulting from genetic changes and alterations in cell behavior, a phenomenon known as epigenetics. Telomeres, protective caps on the ends of chromosomes, regulate both cellular aging and cancer formation. In most cancers, telomerase is upregulated, with the telomerase reverse transcriptase (TERT) enzyme and telomerase RNA component (TERC) RNA element contributing to the maintenance of telomere length. Additionally, it is noteworthy that two viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV), utilize telomerase for their replication or persistence in infected cells. Also, TERT and TERC may play major roles in cancer not related to telomere biology. They are involved in the regulation of gene expression, signal transduction pathways, cellular metabolism, or even immune response modulation. Furthermore, the crosstalk between TERT, TERC, RNA-binding proteins, and microRNAs contributes to a greater extent to cancer biology. To understand the multifaceted roles played by TERT and TERC in cancer and viral life cycles, and then to develop effective therapeutic strategies against these diseases, are fundamental for this goal. By investigating deeply, the complicated mechanisms and relationships between TERT and TERC, scientists will open the doors to new therapies. In its analysis, the review emphasizes the significance of gaining insight into the multifaceted roles that TERT and TERC play in cancer pathogenesis, as well as their involvement in the viral life cycle for designing effective anticancer therapy approaches.

Combination of metformin and phenformin synergistically inhibits proliferation and hTERT expression in human breast cancer cells.

OBJECTIVES: Breast cancer remains a global challenge, and further chemopreventive therapies are still immediately required. Emerging evidence has revealed the potent anti-cancer effects of biguanides, Metformin (MET) and phenformin (PHE). Thus, to explore an efficient chemopreventive strategy for breast cancer, the antiproliferative effects of the combination of MET and PHE against breast cancer cells were assessed. MATERIALS AND METHODS: Cytotoxicity of the drugs individually and in combination against T47D and MDA-MB-231 breast cancer cells were assessed using MTT assay and the median-effect method was used to analyze the precise nature of the interaction between MET and PHE. Besides, the expression levels of hTERT after 48 hr drug exposure were determined using qRT-PCR. RESULTS: Based on the cytotoxicity assay, both MET and PHE further inhibited the growth of MDA-MB-231 cells compared with T47D cells. It was found that MET+PHE reduced the IC50s of MET and PHE in both cells drastically more than the single treatments in a synergistic manner. Importantly, MET+PHE showed higher antiproliferative effect with smaller IC50 values against MDA-MB-231 cells than against T47D cells. Real-time PCR results revealed that hTERT expression was significantly reduced in both breast cancer cell lines treated with MET+PHE than the single treatments. In comparison between two types of breast cancer cells, it was detected that MET+PHE could further decline hTERT expression in MDA-MB-231cells than in T47D cells (P<0.001). CONCLUSION: It is speculated that the combination of MET and PHE may be a promising and convenient approach to improve the efficiency of breast cancer treatment.speculated that the combination of MET and PHE may be a promising and convenient approach to improve the efficiency of breast cancer treatment.

Synergistic Anti-proliferative Effects of Metformin and Silibinin Combination on T47D Breast Cancer Cells via hTERT and Cyclin D1 Inhibition.

BACKGROUND: There is a growing body of data that chemotherapeutic combination strategies would be more effective in reducing drug toxicity, inhibiting tumor progression in comparison to either drug alone. OBJECTIVE: To explore a chemopreventive strategy for improving breast cancer treatment efficacy, the anticancer effects of a combination of Metformin (MET) and Silibinin (SIL) were investigated in T47D breast cancer cells. MATERIALS AND METHODS: Cytotoxicity of the drugs individually and in combination was evaluated using MTT assay. The precise nature of the interaction between MET and SIL was further analyzed through the median-effect method. In addition, qRT-PCR was applied to determine the expression levels of hTERT and cyclin D1 genes after 48 h drug exposure. RESULTS: MTT assays showed that MET and SIL individually inhibited the cell viability in a dose and time-dependent manner, and the obtained combination indices (CIs) were<1 for all the combination treatments, indicating that the anticancer agents synergistically induced growth inhibition in the breast cancer cells. qPCR findings revealed that the drug combination also synergistically down-regulated the expression levels of hTERT and cyclin D1 at all used concentrations compared with the drugs used alone after 48 h treatment (P≤0.05). CONCLUSION: The results provide evidence that synergistic antiproliferative effects of MET and SIL, linking to the down-regulation of Cyclin D1 and hTERT genes, and propose that MET+SIL may have therapeutic value in breast cancer therapy.

Synergistic Growth Inhibitory Effects of Chrysin and Metformin Combination on Breast Cancer Cells through hTERT and Cyclin D1 Suppression

Objective: To explore the possibility of a novel chemopreventive strategy for improving breast cancer treatment, the anticancer effects of a combination two natural compounds, Chrysin and Metformin, against T47D breast cancer cells were investigated. Materials and Methods: After treatment of T47D cells with Metformin, Chrysin and the two drugs in combination, toxicity to cancer cells was evaluated by MTT assay. Real time PCR was then used to determine the expression levels of hTERT and cyclin D1 genes. Results: The MTT test findings showed that the combination of metformin and chrysin had high synergistic effects in killing cancer cells. In addition PCR demonstrated a significant decrease in cyclin D1 and hTERT gene expression in the T47D breast cancer cell line. Conclusion: The conmbination of metformin and chrysin suppressing hTERT and cyclin D1 gene expression might offer an appropriate approach for breast cancer therapy.