Reversal by transferrin of growth-inhibitory effect of suramin on hormone-refractory human prostate cancer cells.
BACKGROUND
The second leading cause of cancer-related deaths in American men is metastatic hormone-refractory adenocarcinoma of the prostate, for which there is currently no effective treatment. Transferrin is abundant in bone stroma and has been found to stimulate models of hormone-refractory metastatic prostate cancer. Suramin, a compound that has been used to treat metastatic prostate cancer, has been demonstrated to antagonize the binding of transferrin to the transferrin receptor and to suppress uptake of iron by hematopoietic cells.


OBJECTIVE
The purpose of our study was to determine whether transferrin may reverse the inhibitory action of suramin on metastatic prostate-derived cell lines.


METHODS
Five human prostate cell lines (PC-3, PC-3M, DU-145, TSU-Pr1, and LNCaP) derived from metastatic deposits were examined for response to growth stimulation by apotransferrin, for the presence of transferrin receptors by binding of 125I-labeled transferrin, and for relative transferrin receptor messenger RNA (mRNA) content by ribonuclease protection assays. We measured the amount of growth inhibition by suramin in low serum assays to demonstrate maximal inhibition over the apotransferrin to reverse the inhibition of suramin in these tumors.


RESULTS
The results clearly demonstrate that the androgen-insensitive metastatic cell lines (PC-3, PC-3M, DU-145, and TSU-Pr1) demonstrate increased cell numbers when exposed to holotransferrin or apotransferrin, while the androgen-sensitive cell line (LNCaP) did not show any increase. All cell lines demonstrated a similar number of transferrin receptors and transferrin receptor mRNA. We used these maximally inhibitory, but clinically relevant, concentrations of suramin to determine whether transferrin could reverse the inhibition, and it did, but only in the androgen-insensitive metastatic lines. Indeed, in the PC-3 cells, inhibition turned to stimulation with the addition of transferrin, and even at the highest concentration of suramin tested, 400 microM, a concentration that would be toxic to patients, the amount of inhibition by suramin was still reduced by more than 50% by transferrin in TSU-Pr1 cells. In the androgen-sensitive LNCaP cells, however, transferrin had limited ability to block the inhibitory activity of suramin.


CONCLUSIONS
Concentrations of tumor-stimulating factors, such as transferrin, in the metastatic microenvironment need to be taken into consideration in the use of suramin and suramin-like derivatives. Novel strategies need to be identified that will negate the action of transferrin on androgen-insensitive cells.
Donat
S M
SM
Urologic Oncology Research Laboratory, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Powell
C T
CT
Israeli
R S
RS
Fair
W R
WR
Heston
W D
WD
D000728:Androgens / Q000502:physiology*; D001059:Apoproteins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis; D011990:Receptors, Transferrin / Q000032:analysis / Q000235:genetics; D013498:Suramin / Q000037:antagonists & inhibitors*; D014168:Transferrin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000728:Androgens; D001059:Apoproteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D014168:Transferrin; C028284:apotransferrin; D013498:Suramin