Examples for the first group include sodium butyrate, depsipetide, fenretinide and flavipirodol while the second group includes gossypol, ABT-737, ABT-263, GX15-070 and HA14-1 (reviewed by Kang and Reynold, 2009 [68]). Some of these small molecules belong to yet

another class of drugs called BH3 mimetics, so named because they mimic the binding of the BH3-only proteins to the hydrophobic groove of anti-apoptotic proteins of the Bcl-2 family. One classical example of a BH3 mimetic is ABT-737, which inhibits anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-W. It was shown to exhibit cytotoxicity in lymphoma, small cell lung carcinoma cell line and primary patient-derived cells and caused regression of established tumours in animal models with a high percentage of cure [69]. Other Selleckchem GS-4997 BH3 mimetics such as ATF4, ATF3 and NOXA have been reported to bind to GSK2399872A and inhibit Mcl-1 [70]. 4.1.2 Silencing the anti-apoptotic proteins/genes Rather than using drugs or therapeutic agents to inhibit the anti-apoptotic members of the Bcl-2 family, some studies have demonstrated that by silencing genes coding

for the Bcl-2 family of anti-apoptotic proteins, an increase in apoptosis could be achieved. For example, the use of Bcl-2 specific siRNA had been shown to specifically inhibit the expression of target gene in vitro and in vivo with anti-proliferative and pro-apoptotic effects observed in pancreatic carcinoma cells [71]. On http://www.selleck.co.jp/products/CHIR-99021.html the other hand, Wu et al demonstrated that by silencing Bmi-1 in MCF breast cancer cells, the expression of pAkt and Bcl-2 was downregulated, rendering these cells more sensitive to doxorubicin as evidenced by an increase in apoptotic cells in vitro and in vivo [72]. 4.2 Targeting p53 Many p53-based strategies have been investigated for cancer treatment. Generally, these can be classified into three broad categories: 1) gene therapy, 2) drug therapy and 3) immunotherapy. 4.2.1 p53-based gene

therapy The first report of p53 gene therapy in 1996 investigated the use of a wild-type p53 gene containing retroviral vector injected into tumour cells of non-small cell lung carcinoma derived from patients and showed that the use of p53-based gene therapy may be feasible [73]. As the use of the p53 gene alone was not enough to FK228 cell line eliminate all tumour cells, later studies have investigated the use of p53 gene therapy concurrently with other anticancer strategies. For example, the introduction of wild-type p53 gene has been shown to sensitise tumour cells of head and neck, colorectal and prostate cancers and glioma to ionising radiation [74]. Although a few studies managed to go as far as phase III clinical trials, no final approval from the FDA has been granted so far [75]. Another interesting p53 gene-based strategy was the use of engineered viruses to eliminate p53-deficient cells.