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Levels of Phospholipid Metabolites in Breast Cancer Cells Treated with Antimitotic Drugs

A ³¹P-Magnetic Resonance Spectroscopy Study¹

Department of Pharmacology, Faculty of Medicine [M. S., I. R.], and David R. Bloom Center for Pharmacy [I. R.], The Hebrew University, Jerusalem 91120; Human Biology Research Center, Hadassah Medical Center, Jerusalem 91120 [E. B.]; and Advanced Technology Center, Sheba Medical Center, Tel Hashomer 52621 [J. S. C., Y. M.], Israel

Magnetic resonance spectroscopy (MRS) methods have provided valuable information on cancer cell metabolism. In this study, we characterized the ³¹P-MR spectra of breast cancer cell lines exhibiting differences in hormonal response, estrogen receptors (positive/negative), and metastatic potential. A correlation was made between the cytotoxic effect of antimitotic drugs and changes in cell metabolism pattern. Because most anticancer drugs are more effective on proliferating cells, our study attempted to elucidate the metabolic profile and specific metabolic changes associated with the effect of anticancer drugs on proliferating breast cancer cell lines. Accordingly, for the ³¹P-MRS experiments, cells were embedded in Matrigel to preserve their proliferation profile and ability to absorb drugs. The MRS studies of untreated cells indicated that the levels of phosphodiesters and uridine diphosphosugar metabolites were significantly higher in estrogen receptor-positive and low metastatic potential cell lines. ³¹P-MRS observations revealed a correlation between the mode of action of anticancer drugs and the observed changes in cell metabolic profiles. When cells were treated with antimicrotubule drugs (paclitaxel, vincristine, colchicine, nocodazole), but not with methotrexate and doxorubicin, a profound elevation of intracellular glycerophosphorylcholine (GPC) was recorded that was not associated with changes in phospholipid composition of cell membrane. Remarkably, the rate of elevation of intracellular GPC was much faster in cell population synchronized at G₂-M compared with the unsynchronized cells. The steady-state level of GPC for paclitaxel-treated cells was reached after 4 h for synchronized cells and after 24 h (approximate duration of one cell cycle) for the unsynchronized ones. These observations may indicate a correlation between microtubule status and cellular phospholipid metabolism. This study demonstrates that ³¹P-MRS may have diagnostic value for treatment decisions of breast cancer and reveals new aspects of the mechanism of action of antimicrotubule drugs.

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