Pamidronate resistance and associated low ras levels in breast cancer cells: a role for combinatorial therapy.
To identify markers sensitive to inhibitors of the farnesylation pathway, we used 3 breast cancer cell lines (SKBR-3, MDA-175, and MDA-231) to evaluate the in vitro effects of pamidronate, an inhibitor of farnesyl diphosphate synthase. In response to pamidronate, there was significant inhibition of cell proliferation in MDA-231 and SKBR-3 cells, compared to MDA-175 cells. This correlated with their respective basal levels of N-ras and H-ras. N-ras and H-ras protein levels were both reduced in MDA-231 cells, and to lesser extent in SKBR-3 cells, following exposure to pamidronate, whereas these markers were not altered in MDA-175 cells. Combinatorial therapy with pamidronate and Gleevec, an inhibitor of several tyrosine kinases; Velcade, a proteasome inhibitor; or rapamycin, an inhibitor of the mammalian target of rapamycin (m-TOR) all showed additive effects in causing proliferative inhibition in MDA-175 cells. In summary, resistance to pamidronate may result from low levels of GTPase-activating proteins, such as N-ras and H-ras, in tumor cells. Combinatorial therapies directed against other signaling pathways, not dependent upon ras, may be required to overcome such resistance.
Department of Laboratory Medicine, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Ping L
PL
Zhang
Mingyue
M
Lun
Nava
N
Siegelmann-Danieli
Thomas M
TM
Blasick
Robert E
RE
Brown
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000627:therapeutic use*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D000077268:Pamidronate; D010879:Piperazines / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D018631:ras Proteins / Q000378:metabolism*
D001549:Benzamides; D001897:Boronic Acids; D004164:Diphosphonates; D004338:Drug Combinations; D010879:Piperazines; D011719:Pyrazines; D011743:Pyrimidines; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D018631:ras Proteins; D000077268:Pamidronate; D020123:Sirolimus