Analysis Of The Effects Of Metformin Administered Alone Or In Combined Treatments In Colorectal Cancer

The aim of this project was to investigate the anticancer activity of the anti-diabetic drug metformin, individually or combined in various settings with chemotherapy, on in vitro models of colorectal cancer (CRC). I found that metformin reduced cell proliferation by inducing cell cycle arrest in the G0/G1 phase, but did not lead to cell death. The anti-proliferative action of metformin resulted mediated by the inactivation of the mTOR pathway and of IGF1R protein. However, the drug only transiently arrested cell growth, since its effects were reversed after drug removal. When I combined the biguanide with the chemotherapy drugs commonly used to treat CRC I observed different responses in the cell lines analysed that reflected their genetic background and their different sensitivities to both the biguanide and chemotherapy. I found that metformin added before chemotherapy drugs antagonised their effects in the majority of the treatments. On the contrary, its administration after long chemotherapeutic treatments significantly reduced the cell viability. I noted that metformin better inhibits cell proliferation in cell lines with rapid growth. I have also assessed the dual treatment combination of metformin with different drugs that target specific genes or proteins (targeted therapies), focusing on BRAF-mutant cell lines. For most of the tested treatments the simultaneous administration of metformin and target drugs gave no advantages over the single drugs, and often resulted in antagonism. Overall, our results show that although further investigations are still needed to elucidate the results of the treaments including metformin, these data suggest that caution should be used in administering chemotherapy to indviduals taking metformin.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2017

Author dc:creator

• Maiorana, Maria Valeria

Language dc:language

en