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Annals of Clinical & Laboratory Science 34:263-270 (2004)
© 2004 Association of Clinical Scientists

Review

Pamidronate Resistance and Associated Low Ras Levels in Breast Cancer Cells: A Role for Combinatorial Therapy

Ping L. Zhang1,3, Mingyue Lun3, Nava Siegelmann-Danieli2, Thomas M. Blasick3 and Robert E. Brown1
1 Department of Laboratory Medicine, 2 Department of Adult Hematology and Oncology, and 3 Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania

Address correspondence to Robert E. Brown, M.D., Department of Laboratory Medicine, Geisinger Medical Center, 100 North Academy Ave., Danville, PA 17822, USA; tel 570 271 6333; fax 570 271 6105; e-mail: rebrown{at}geisinger.edu.

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.

Keywords: pamidronate, H-ras, N-ras, apoptosis, breast cancer, Gleevec, Velcade




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