Antisense oligonucleotides targeted to the human alpha folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment.
Folates are essential for cell survival and are required for numerous biochemical processes. The human alpha isoform folate receptor (alphahFR) 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 alphahFR is not detected inmost normal tissues. In contrast, high levels of the expression of alphahFR have been reported in a variety of cancer cells. The significance of alphahFR 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 alphahFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of alphahFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the alphahFR gene sequences were found to reduce newly synthesized alphahFR protein up to 60%. To examine the effect of alphahFR 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 alphahFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that alphahFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of alphahFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.
Jhaveri
Mona S
MS
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia 20007-2197, USA.
Rait
Antonina S
AS
Chung
Koong-Nah
KN
Trepel
Jane B
JB
Chang
Esther H
EH
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000235:genetics*; D014168:Transferrin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D011956:Receptors, Cell Surface; D014168:Transferrin; D004317:Doxorubicin; D005492:Folic Acid