Nucleoside analogs are used as chemotherapeutic options for the treatment of
platinum-resistant
ovarian cancers. Human concentrative
nucleoside transporter 1 (hCNT1) is implicated in sensitizing solid
tumors to
nucleoside analogs although its role in determining
drug efficacy in
ovarian cancers remains unclear. Here we examined the functional expression of hCNT1 and compared its contributions toward
gemcitabine efficacy in histological subtypes of
ovarian cancer. Radioactivity analysis identified hCNT1-mediated (3)H-gemcitabine transport in
ovarian cancer cells to be significantly reduced compared with that of normal ovarian surface epithelial cells. Biochemical and immunocytochemical analysis identified that unlike normal ovarian cells which expressed high levels of hCNT1 at the apical cell surface, the transporter was either diminished in expression and/or mislocalized in cell lines of various subtypes of
ovarian cancer. Retroviral expression of hCNT1 selectively rescued
gemcitabine transport in cell lines representing serous,
teratocarcinoma, and endometrioid subtypes, but not clear cell
carcinoma (CCC). In addition, exogenous hCNT1 predominantly accumulated in intracytoplasmic vesicles in CCC suggesting defective cellular trafficking of hCNT1 as a contributing factor to transport deficiency. Despite diminution of hCNT1 transport in the majority of
ovarian cancers and apparent trafficking defects with CCC, the chemotherapeutic efficacy of
gemcitabine was broadly enhanced in all subtypes when delivered via engineered nanoparticles (NPs). Additionally, by bypassing the transport requirement, the delivery of a
gemcitabine-
cisplatin combination in NP formulation increased their synergistic interactions. These findings uncover hCNT1 as a putative determinant for
nucleoside analog chemoresistance in
ovarian cancer and may help rationalize
drug selection and delivery strategies for various histological subtypes of
ovarian cancer.