Browsing by Subject "metformin"
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(2020)Breast cancer remains as the leading cause of cancer deaths among women. Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes and lacks targetable receptors, consequently, cannot be treated with current hormone of anti-HER2 targeting therapies. Thus, there is a need for discovering novel and well-tolerated therapies. MYC is a proto-oncogene and a transcription factor, that is frequently amplified and overexpressed in breast cancers. MYC is involved in many cellular processes promoting cell proliferation, however, overexpression of MYC can also sensitize cells to replicative stress and apoptotic cell death. In our previous studies we have shown that pharmacological activation of AMPK, a cellular energy sensor, synergises with Bcl-2 family inhibitors, such as navitoclax and venetoclax, and activates MYC-dependent apoptosis in breast cancer cell lines, transgenic mouse models of MYC-dependent mammary tumorigenesis and in MYC-high patient-derived explant cultures (PDECs). In subsequent study we observed, that indirect AMPK activator metformin alone inhibited tumor growth in vivo, but did not induce apoptosis in mouse tumors or in PDECs. Metformin, a type II diabetes mellitus drug, has shown anti-cancer effects in some population studies and is under investigation for a cancer therapies, however the whole mechanism of action in cancer is still not well-known. To elucidate metformin’s effects on MYC overexpressing triple-negative breast cancer cells, I will present, that metformin has anti-proliferative effects and show that long term metformin treatment induces senescence biomarkers in MYC-high TNBC breast cancer cell lines. To study metformin's short and long-term anti-proliferative activity, cell proliferation during and after drug treatment was investigated, which showed, that metformin’s effects do not seem to persist long after drug withdrawal. In conclusion, the key observation of this thesis was, that metformin does inhibit the proliferation of MYC overexpressing cancer cells and presents a senescence phenotype that possibly can be exploited to find new targeted therapies for triple-negative breast cancer patients.
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(2020)Diabetic ovarian cancer patients who take metformin as part of their anti-diabetic medication generally respond better to DNA-damaging cancer treatment. The molecular mechanisms of the anti-cancer effects of metformin are currently being investigated, but they remain poorly elucidated. Not much is understood about the metformin effect on DNA damage in ovarian cancer cells, where it is of particular importance. When chemotherapy-induced double-stranded DNA breaks are unrepaired, cells reach a point when they cannot tolerate the accumulated DNA damage and die. However, some ovarian cancer cells efficiently employ DNA repair mechanisms, the most prominent being homologous recombination (HR), to overcome DNA damage. Efficient HR causes chemoresistance. An important question is whether metformin has the ability to induce the HR-deficient state in cancer cells, thereby sensitizing them to treatment. This study did not examine HR directly, but it assessed HR indirectly by observing the effect of metformin on recovery from DNA damage in two ovarian cancer cell lines: OVCAR4 (HR-proficient) and Kuramochi (HR-deficient). Additionally, this study evaluated the metformin effect on cell proliferation and apoptosis. OVCAR4 and Kuramochi cells were exposed to varying metformin concentrations (0,5 mM, 5 mM, 10 mM, 15 mM, 20 mM and 25 mM) and for varying durations (24 hours and 48 hours). This study also tested how metformin pretreatment affected the cells’ ability to repair externally (ionizing irradiation) induced DNA damage. The cells were imaged with a high-content imaging system, and percentages of nuclei that were positive for markers for different cellular processes (i.e., DNA damage, proliferation, and apoptosis) were calculated. The study found that only high metformin concentrations, such as 20 mM were able to increase DNA damage and reduce cell proliferation in HR-proficient OVCAR4 cells, both non-irradiated and irradiated. The HR-deficient Kuramochi cell line was generally more sensitive to metformin, particularly with regards to DNA damage, which increased using metformin concentrations < 20 mM. However, 20 mM concentration resulted in the most significant effects. Similarly, only high metformin concentration (25 mM) increased apoptosis, although data were obtained only for a limited number of Kuramochi cells. More experiments on apoptosis would be beneficial. Also, more extensive experiments for the irradiation part are needed to validate these preliminary findings, as well as examining whether high metformin concentrations (> 20 mM) affect specifically the HR-mediated DNA repair pathway.
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(2022)Breast cancer is the most common cancer in the world and among women the most cancer deaths causing cancer. MYC is a proto-oncogene, which becomes oncogenic when its expression is deregulated in cancer. MYC is commonly overexpressed in human tumours and this alteration is associated with aggressive cancer phenotype. Furthermore, alterations in the MYC network have been found in the great majority of breast cancers. MYC promotes mitochondrial apoptosis causing a cancer vulnerability, however, in cancer cells the apoptosis is often prevented by antiapoptotic BCL-2 family members. In this study, cell viability and cell death analysis of treated triple-negative breast cancer cell lines together with dendritic cell activation experiments were conducted. This study aimed to find the most potent BCL-2 family antagonist (BH3 mimetic) to combine with metformin to overcome the antiapoptotic BCL-2 family proteins inhibition of MYC-induced apoptosis. In addition, this study determined whether the combinations could induce immunogenic cell death to further intensify cancer cell killing through anti-tumour immunity. In this study, BH3 mimetics combined with metformin were found to induce cell death and reduce cell viability in TNBC cell lines. In addition, metformin and BH3 mimetics were found to activate dendritic cells directly and through immunogenic cell death of cancer cells. However, no MYC-dependent cell death or immunogenic cell death were observed, and this study was unable to indicate the most potent BH3 mimetic to combine with metformin.
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