Nuclear sparing of anthracycline chemotherapeutics and chemoresistance in cancer

Anthracyclines are one of the most potent and widely used chemotherapeutics in cancer treatment. Their main anti-cancer mechanisms of action are to bind to DNA and topoisomerase II enzyme, causing DNA damage. Hence, the intranuclear concentration of anthracyclines is an important determinant of their anticancer efficacy. However, nuclear accumulation cannot be observed in resistant cells, known as "nuclear sparing". To overcome resistance to anthracyclines, mechanisms of nuclear sparing should be clarified. P-gps are drug efflux pumps localized in the cellular membrane which decrease the intracytoplasmic concentration of various drug molecules. Recent studies have shown that P-gp can also be localized in the nucleus. In this thesis, we investigated the role of nuclear P-glycoproteins (P-gp) in the nuclear sparing of doxorubicin and chemoresistance in gastric cancer since it is one of the most chemo-resistant cancers. We developed gastric adenocarcinoma cell lines with varying degrees of resistance to doxorubicin. In these cells, we observed that increased doxorubicin resistance was significantly correlated with the increase in the nuclear P-gp. To validate the role of nuclear P-gp in nuclear sparing and chemoresistance, we overexpressed P-gp in parental cells and suppressed P-gp in our resistant cells. We were able to increase the cell's resistance to doxorubicin in parental cells while reversing resistance by silencing P-gp in resistant cells. Our findings suggest that doxorubicin can induce the nuclear translocation of P-gp by a process where nuclear localization signals are involved. In conclusion, increased expression of nuclear P-gps may be a pivotal mechanism for nuclear sparing and acquired resistance in gastric cancer.