Antisense oligonucleotides targeted to the human α folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment

Abstract

Abstract Folates are essential for cell survival and are required for numerous biochemical processes. The human α isoform folate receptor (αhFR) has a very high affinity for folic acid and is considered an essential component in the cellular accumulation of folates and folate analogues used in chemotherapy. The expression of αhFR is not detected inmost normal tissues. In contrast, high levels of the expression of αhFR have been reported in a variety of cancer cells. The significance of αhFR overexpression in malignant tissues has not been elucidated, but it is possible that it promotes cell proliferation not only by mediating folate uptake but also by generating other regulatory signals. The purpose of the present study was to evaluate αhFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of αhFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the αhFR gene sequences were found to reduce newly synthesized αhFR protein up to 60%. To examine the effect of αhFR antisense ODNs in a panel of cultured human breast cancer cell lines, we used a tumor cell–targeted, transferrin-liposome–mediated delivery system. The data show that αhFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that αhFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of αhFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.