Targeting the Transforming Growth Factor-beta Signaling in Cancer Therapy

TGF-beta pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-beta (TGF-beta) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-beta related functional contexts. This review discusses the molecular mechanism of the TGF-beta pathway and describes the different ways of tumor suppression and promotion by TGF-beta. In the last part of the review, the data on targeting TGF-beta pathway for cancer treatment is assessed. The TGF-beta inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.

Anti-Cancer Effect of 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide in MCF-7 Human Breast Cancer

OBJECTIVES: In recent years, a number of structurally diverse Histone deacetylase (HDAC) inhibitors have been identified and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. This study aimed at investigating the anti-tumor activity of newly synthesized HDAC inhibitor, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide (IN-2001) using human breast cancer cells. METHODS: We have synthesized a new HDAC inhibitor, IN-2001, and cell proliferation inhibition assay with this chemical in estrogen receptor-positive human breast cancer MCF-7 cells. Cell cycle analysis on MCF-7 cells treated with IN-2001 was carried out by flow cytometry and gene expression was measured by RT-PCR. RESULTS: In MCF-7 cells IN-2001 showed remarkable anti-proliferative effects in a dose- and time-dependent manner. In MCF-7 cells, IN-2001 showed a more potent growth inhibitory effect than that of suberoylanilide hydroxamic acid. These growth inhibitory effects were related to the cell cycle arrest and induction of apoptosis. IN-2001 showed accumulation of cells at G2/M phase and of the sub-G1 population in a time-dependent manner, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with HDAC inhibitor-mediated induction of CDK inhibitor expression. In MCF-7 cells, IN-2001 significantly increased p21WAF1 expression. CONCLUSIONS: In summary, cyclin-dependent kinase (CDK) induced growth inhibition, possibly through modulation of cell cycle and apoptosis regulatory proteins, such as CDK inhibitors, and cyclins. Taken together, these results provide an insight into the utility of HDAC inhibitors as a novel chemotherapeutic regime for hormone-sensitive and insensitive breast cancer.