Chemosensitization of Breast Cancer Cells to Chemotherapeutic Agents by 3,3'-Diindolylmethane (DIM)

摘要

Constitutive activation of Akt or NF-B has been reported to play a role in de novo resistance of cancer cells to chemotherapeutic agents, which is a major cause of treatment failure in cancer chemotherapy. Previous studies have shown that 3, 3-diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of indole-3-carbinol (I3C), is a potent inducer of apoptosis, inhibitor of tumor angiogenesis and inactivator of Akt/NF-B signaling in breast cancer cells. However, little is known regarding the inactivation of Akt/NF-B that leads to chemosensitization of breast cancer cells to chemotherapeutic agents such as Taxotere. Therefore, we examined whether the inactivation Akt/NF- B signaling caused by B-DIM could sensitize breast cancer cells to chemotherapeutic agents both in vitro as well as in vivo. MDA-MB-231 cells were simultaneously treated with 15 to 45 M B-DIM and 0.5 to 1.0 nM Taxotere for 24 to 72 hours. Cell growth inhibition assay, apoptosis assay, EMSA, and Western blotting were performed. The combination treatment of 30 M B-DIM with 1.0 nM Taxotere elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced greater apoptosis in MDA-MB-231 cells compared with single agents. Moreover, we found that NF-B activity was significantly decreased in cells treated with B-DIM and Taxotere. We also have tested our hypothesis using transfection studies followed by combination treatment with B-DIM/Taxotere and found that combination treatment significantly inhibited cell growth and induced apoptosis in MDA-MB-231 breast cancer cells mediated by the inactivation of NF-B, a specific target in vitro and in vivo. These results were also supported by animal experiments which clearly showed that BDIM sensitized the breast tumors to Taxotere which resulted in greater anti-tumor activity mediated by the inhibition of Akt and NF-B.