Induction of apoptosis in estrogen dependent and independent breast cancer cells by the marine terpenoid dehydrothyrsiferol

Abstract

Breast cancer (BCA) represents the highest incidence of death in 35- to 60-year-old women. Above all, hormone unresponsive BCA is still associated with poorer prognosis than hormone receptor expressing malign, mammary tumors. There is a consistent need for effective compounds to treat especially the first variant of this disease. Therefore, we investigated the cytotoxic effects of the marine polyether triterpenoid dehydrothyrsiferol (DT) in four BCA cell lines. Annexin V labeling revealed higher rates of DT-induced apoptosis in hormone insensitive than in estrogen receptor expressing cells. Flow cytometric analysis of combined DNA fragmentation and total DNA labeling allowed us to ascribe apoptotic cells to their cell cycle stage. Although, high cell mortality was detected in mitogen dependent G 1-phase, time, concentration, and cell line dependent populations of apoptotic cells were also found to be of S-phase and G 2/M-phase origin. These results suggest that the induction of apoptosis by DT might be transduced through more than one effector pathway. Cell cycle distributions and 5-bromo-2′-deoxyuridine incorporation varied in a treatment dependent manner and differed from control experiments with colchicine and doxorubicin which exclude that DT functions as a mitosis inhibitor. In summary, we propose that DT might be an interesting candidate for an antitumor drug development regimen.