Cytotoxicity effects Of combination Of PRIMA-1met and etoposide on non-small cell lung cancer (NSCLC) cell lines A549 (Wild Type-p53) and NCI-H1975 (Mutant-p53)

Cancer is a common disease with increasing cases each year. Although progression has been made in many cancer treatments with an increasing success rate in the current chemotherapy treatment, the side effects associated with chemotherapy and resistance to the chemotherapeutic drug have demonstrated the need for novelty to investigate new treatments alternative to chemotherapy. Therefore, chemotherapy is combined with different cancer treatments. In addition, individual and tumor specific drug targeting therapies are preferred among many potential alternative therapies because they target the pathway of apoptosis. The tumor suppressor protein, p53, is a transcription factor involved in controlling cell cycle and apoptosis and regulating cell genomic integrity. P53 protein helps prevent the development of tumors by preventing the division of mutated or damaged DNA. P53 is called the guardian of the genome because it is crucial for regulating cell division and preventing tumor formation, and is the most frequently mutated tumor suppressor protein in solid tumors. Since mutant p53 is highly associated with late-stage malignancy and drug resistance, it has been considered a potential target for the development of new cancer therapies. Therefore, pharmacological reactivation of mutant-p53 has emerged as a promising strategy for developing cancer therapies. PRIMA-1met has been described as one of the most promising drugs for clinical use in restoring wild type functions to mutant p53. In combination therapy studies to date, induction of mutant-p53 levels with chemotherapeutic drugs has shown the possibility of increasing the sensitivity of tumor cells to PRIMA-1met. Thus, the combination of PRIMA-1met with currently used chemotherapeutic drugs may represent a new and more effective therapeutic strategy for the treatment of mutant p53-carrying tumors. Based on all the information obtained from the literature, in this thesis, it was aimed to investigate the anticancer effect of PRIMA-1met with Etoposide, a chemotherapeutic drug, in NCI-H1975 (p53-mutant) and A549 (p53-wild type) human NSCLC (Non-Small Cell Lung Cancer) cell lines. Firstly, the cytotoxic effect of PRIMA-1met and Etoposide alone was evaluated. Subsequently, doses of 20 and 40 µM were selected from the effective doses of Etoposide at 24 h and the cytotoxic effects of their combination with Prima-1met doses were evaluated. It was observed that treatment of etoposide increased the efficacy of PRIMA-1met in A549 and NCI-H1975 cells. In this context, this thesis study supported the combined studies of PRIMA-1met in the other types of cancer with antineoplastic agents and showed that combined treatment with Etoposide in NSCLC may be an alternative treatment option.