ABSTRACT: Cancer is characterised as a set of diseases that is involved in uncontrolled cell growth with the ability to invade or spread to the other part of the body. Carcinogenesis is recognized as a process through aggregation of genetic and epigenetic changes in normal cell that ultimately leading to unlimited growth proliferation and invasion. Pancreatic neuroendocrine tumour (PNET) is a rare tumour that arise from neuroendocrine gland, occurs in various part of the body. The prevalence rate of PNETs is near about 25–30 per 100,000 population in the United States and according to Surveillance Epidemiology and End Results (SEER), the incidence rate of PNETs increased five-fold from 1973 to 2011. PNETs comprises approximately 7% of all types of cancer in the pancreas. Normally, 5 years survival rate of PNETs near about 42%. PNETs is a heterogenous group of disorder with less 5 years survival rate due to lack of effective therapeutic options for patients with advanced stages, absence of symptomatology specially in case of non-functional PNETs and also to the phenomenon of chemoresistance, dependent on multiple mechanisms. Recent data shows that incidence rate of this tumour increases as a result of germline genetic mutations. Concerning to genetic change, it is very important to explain the differences that occurs at the level of chemoresistance. The treatment plan of the PNETs varies on type, location and aggressiveness of the tumour. Surgery is the only curative treatment in early stage but in advanced stages chemotherapy and radiotherapy are the most palliative treatment option of PNETs. Chemotherapy which is mainly based cisplatin combined with capecitabine and the response rate of treatment is near about 30%. Cisplatin is responsible for the formation of DNA adducts, leading to DNA damage, and induces generation of ROS, that consequently leads to oxidative stress, cell damage and death. Glutathione (GSH) plays an important role in the maintenance of intercellular redox balance and detoxification. Chemoresistance can be based on the alteration of the detoxification mechanisms and GSH system has been pointed as one of the most important. Cysteine is a rate limitant substrate for GSH synthesis, and xCT cyst(e)ine transporter is implicated in cancer severity and chemoresistance. The Hypothesis of the project is: the disruption of xCT and uptake of cysteine leads to the reversal of resistance to alkylating agents in pancreatic neuroendocrine tumours (PNETs). To accomplish the hypothesis we defined 3 aims: 1st aim will be to address the expression of xCT in PNETs cell lines, and the modulation of xCT expression by cysteine and cisplatin; 2nd aim will be focused on the effect of xCT inhibition in PNETs cell death, using erastin and sulfasalazine, and 3rd aim will be focused on the effect of new nanoformulations in order to disturb cysteine uptake (Sechry and Sechry@PUREG4-FA) and glutathione synthesis (BSO@PUREG4-FA). Our work allowed to reveal the role of xCT transporter and the role of cysteine in PNETs cell line resistance. This cell line showing different response patterns in cysteine transporters activity helped to reveal the differences of the transporter in chemoresistance mechanism. It also showed that besides xCT transporter other cysteine transporter such as EAAT3 also appeared to be involved in the dynamics of chemoresistance mechanism. This work was also important to undercover the effect of new nanoformulations in order to disturb cysteine uptake by using SeChry and GSH synthesis by using BSO in PNETs cell lines. SeChry, but not SeChry@PUREG4-FA, induced cell death in BON-1 cell lines. SeChry cytotoxicity can be selective for cancer cells and this was taken in consideration in our new strategy by using SeChry@PUREG4-FA, however the assay was not successful and new markers for targeted delivery must be investigated in PNETs. BSO@PUREG4-FA induced cell death in combination with platinum salts in PNETs cell lines. Possibly, the use of folate functionalised particles will help to bypass the critical step in the non-specific delivery of BSO to non-cancer cell. The targeted BSO delivery to cancer cells can be explored as a novel strategy in cancer therapeutics. Moreover, more assays with cancer and non-cancer cells must be done in order to determine if folate receptor is in fact a suitable target to delivery drugs to PNETS cells, and find new and more specific targets.