Arsenic trioxide inhibited the growth of human breast cancer cells via cell cycle arrest and apoptosis

4850

Abstract:

Breast cancer is a common cancer among women in Hong Kong and world wide. Tamoxifen is the most common drug used to treat breast cancer, which antagonist the effects of estrogen on breast cancer cells, called an “anti-estrogen.” But tamoxifen is low in potency in late stage breast cancer, which is Estrogen Receptor-alpha (ER α) negative.

Arsenic trioxide (As₂O₃) has been explored for medical application in both Western and Chinese societies. Derived from Pishi by sublimation, it constitutes a major ingredient of arsenic compounds in Traditional Chinese Medicine (TCM). In 1990s, As₂O₃ was reported to be effective for treatment of acute promyelocytic leukemia (APL). The arsenic therapy was focused on APL and other leukemia until recently when researchers begin to study its effect on other solid tumor cells.

In present study, we investigate the anti-tumor effects of As₂O₃ on breast cancer, using MDA-MB-231, an ER α negative human breast cancer cell line. The methylthiazoletetrazolium (MTT) assay showed that As₂O₃ inhibited cell proliferation of MDA-MB-231 cellsin a time and dose dependent manner. The IC50 of cells treated with As₂O₃ for 72h was 12.5 µM. A typical ladder pattern was observed in DNA fragmentation assay. Quantification of apoptosis using flow cytometry with Annexin V-PI staining revealed a shift of cell population to the right bottom quadrate in cells treated with As₂O₃. Moreover, the result of cell cycle analysis showed an increase in G2/M phase further indicated that the As₂O₃ inhibited the proliferation of MDA-MB-231 cells via cell cycle arrest or apoptosis. And the involvements of apoptosis and cell cycle arrest were confirmed by the western bolt analysis that: (1) As₂O₃-induced apoptosis was dependent on the extrinsic pathway, as shown by caspase 8 and caspase 3 activation. (2) As₂O₃-induced apoptosis was dependent on the mitochondria intrinsic pathway, as shown by activation of caspase 9, what’s more, decrease of bcl-2 expression, the increase ratio of Bax/bcl-2. (3) As₂O₃ induced cell cycle arrest at G2/M phase, as shown by decrease of cyclin B.

We therefore concluded that arsenic trioxide inhibited the growth of MDA-MB-231 cells via cell cycle arrest and apoptosis