Investigation the effects of combined treatment with temozolomide and gap junction inhibitors on glioblastoma

Glioblastoma, a highly lethal brain cancer with a survival rate of 6.8%. Connexins are gap junction proteins that enable the cell-cell communication. They contribute to drug resistance as well as invasive and metastatic characteristics of cancerous cells. Specifically, Connexin 43 is the most abundant connexin protein in GBM cells which is shown to be involved in chemotherapy resistance. However, the mechanism of Connexin-43 mediated resistance is not revealed, yet. In this thesis, Connexin-43 inhibitors, 18β-GA and oleamide, are combined with Temozolomide (TMZ), a chemotherapeutic agent used in GBM, and the TMZ sensitivity is evaluated when Connexin-43 is inhibited. Also, the changes in the protein expression of drug resistance associated key members are investigated. It is demonstrated that TMZ sensitivity increases with Connexin-43 inhibition. However, when combined with TMZ, 18β-GA presents a more significant decrease in GBM cell viability compared to oleamide. Interestingly, protein expression profile indicates that chemoresistance related molecules are upregulated in combined treatment groups which requires new insights to Connexin-43 inhibition in GBM treatment. KEY WORDS: Glioblastoma, Connexin-43, Chemoresistance, 18b-GA, Oleamide, Temozolomide