As far as we know, CUDC-101 is a multitargetd small-molecular compound which is a potent receptor tyrosine kinase (including EGFR and HER2 et al.) and histone deacetylase (including calss I and class II) inhibitor with extremely low half-inhibitory concentration up to nanomole. However, whether the inhibitory effects of CUDC-101 on receptor tyrosine kinase (RTK) and histone deacetylase (HDACs) are significant additive or synergistic remains unclear. In a study, combined blockage of histone deacetylase and EGFR signaling pathways mediated by two tool compounds, which were named as vorinost (a potent histone deacetylase inhibitor) and erlotinib (an selective EGFR kinase inhibitor), achieves considerably good synergy in the used MDA-MB-468 breast cancer cell line. Experiments suggested that CUDC-101, which has been shown dual receptor tyrosine kinase (RTK) and histone deacetylase (HDACs) inhibitory activities, has also synergistical but similar or/and equal or greater potency against the combined inhibition of these two target signaling pathways compared with the combination index of vorinostat and erlotinib. To further determine the effective synergistic actions of CUDC-101, its growth-inhibitory effects were also tested in other more than fifty cancer cell lines. The results showed that the agent is also efficacious against a wide scope of cancer cell types, including lung cancer, pancreas cancer, liver cancer, as well as colon and breast tumor cell lines. Besides, CUDC-101 also repressed the growth and proliferation of the lapatinib-insensitive breast cancer cell line MDA-MB-231 which is triple-negative including estrogen receptor negative, progesterone receptor negative, and HER2 negative. It exerts its roles as effectively as lapatinib-sensitive and HER2-overexpressed lines BT-474 and SkBr-3. Meanwhile, the compound prevented the proliferation of lung cancer cell lines including H1975, that are is insensitive to the treatment of erlotinib due to an EGFR-T790M mutation. All of these provide evidences for the idea that using one compound directed against multiple targets improves therapeutic efficacy in patients with cancers mentioned above. [1] TAK-165 is also named as mubritinib which is first originally designed and synthesized by Takeda Chemical Industries in Japan. Mubritinib (TAK 165) (view Fig. 1 for its chemical structure) is validated as a potent human epidermal growth factor receptor 2 (HER2; erbB2) that is classified into one of members of epidermal growth factor receptor tyrosine kinase family, inhibitor with an IC50 of 6nM for the HER2. Many lines of evidences that human epidermal growth factor receptor 2 (HER2) is expressed in bladder cancer cell lines (such as, HT1376, UMUC3 and T24), renal cell carcinoma (RCC) cell lines (ACHN) and androgen-independent prostate cancer cell lines (DU145, LNCaP, LN-REC4) has been reported. However, The results of western blot analysis showed that the expression levels of human epidermal growth factor receptor 2 (HER2) in these cancer cell lines was weak compared with that in breast cancer cell lines BT474 which highly expressed HER2. For the investion of in vitro effectiveness, Mubritinib (TAK-165) treated cells mentioned above for 72 hours at different concentrations. Then the number of cells was counted with a hemocytometer for calculation of IC50 value of TAK-165 against cell lines. The results suggested that TAK-165 blocked the phosphorylation of HER2 and sequentially inhibit its down-stream Akt and MAPK in HER2 strongly expressing BT474 breast cancer. As we known, human epidermal growth factor receptor 2 (HER2) activates its downstream PI3K and MAPK signaling transduction pathways that are associated with apoptosis and growth of cells, respectively. At a low concentration of 0.1 M, the phosphorylation of HER2 was sufficiently prevented by TAK-165 as well as that of Akt and MAPK.[1] References: [1] Cancer Res. 2010 May 1;70(9):3647-56. Related posts: CUDC-101 exerts its potent antiproliferative activity via inhibition of multiple signaling pathways Single-target and multitargted strategies
Please Rate this Article 5 out of 54 out of 53 out of 52 out of 51 out of 5
Not yet Rated
