癌症基因的分子調控及藥物開發(Molecular Regulation and Drug Development of Cancer Genes)

在有絲分裂癌症基因的研究包括Survivin及Securin等,已進行多年的探討,建立人類癌細胞(包括肺癌、大腸癌及乳癌等)會大量表達Survivin蛋白,Cyclin B1/CDC2與p38 MAP kinase可分別為正調控及負調控Survivin基因及蛋白的表現(Chao et al., 2004, JBC),Survivin蛋白會大量表達於癌細胞之有絲分裂期,並會聚集於細胞質分裂期的midbody (Kuo et al., 2004, JBC)。阻斷Survivin基因,會促進抗癌藥物抑制癌細胞的作用(Chao and Liu, 2006, Mol Pharmacol; Lin et al., 2005, Biochem. Pharmacol; Hsiao et al., 2007, TAAP; Chao et al., 2007, Mol Cancer Ther)。癌細胞中Securin的表現也會影響抗癌藥物治療的效果與抗藥性作用(Chao et al., 2006, Toxicol Sci; Chiu et al., 2006, Tox Lett; Chiu et al., 2007, Chem Biol Interact; Chiu et al., 2008, Tox Lett; Liu et al. 2010, J Cell Biochem; Huang et al., 2014, Chem Biol. Interact)

在新藥的研究發展,目前開發出三種新型化合物包括PT262、CR108及SP101。發現PT262是一種新型ROCK抑制劑(Tsai et al., 2011, Biochem Pharmacol)PT262具有抑制肺癌細胞生長及促使細胞凋亡作用,並能阻斷ERK及CDC2的磷酸化作用(Hsu et al., 2008, Cancer Chemther Pharmcol),CR108是一種新型 Vitamin K3衍生物,具有抑制人類乳癌的效果(Yang et al., 2013, TAAP),SP101是一種新型EGFR抑制藥物(Yin et al., 2014, BMCL)。目前持續研究這三種新型化合物的藥理活性及毒理作用,探討是否具有潛力發展成為治療癌症的藥物。

 

References

Yin, KH, Hsieh, YH, Sulake, RS, Wang, SP, Chao, JI*, and Chen, C* (2014) Optimization of the gefitinib analogues with potent anticancer activity. Bioorganic & Medicinal Chemistry Letters, 24: 5247-5250..

Huang, YT, Lin, CI, Chien, PH, Tang, TT, Lin, J, and Chao, JI* (2014) The depletion of securin enhances butein-induced apoptosis and tumor inhibition in human colon cancer. Chemico-Biological Interactions, 220:41-50.

Lai, YJ, Lin, CI, Wang, CL, and Chao, JI* (2014) Expression of survivin and p53 modulates honokiol-induced apoptosis in human colon cancer cells. Journal of Cellular Biochemistry, 115:1888-1899.

Yang, CR, Liao, WS, Wu, YH, Murugan , K, Chen, C*, and Chao, JI* (2013) CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction. Toxicology and Applied Pharmacology, 273: 611-622 

Yu, SY, Liu, HF, Wang, SP, Chang, CC, Tsai, CM, and Chao, JI* (2013) Evidence of securin-mediated resistance of gefitinib-induced apoptosis in human cancer cells. Chemico-Biological Interactions, 203: 412-422.

Tsai, CC, Liu, HF, Hsu, KC, Yang, JM, Chen, C, Liu, KK, Hsu, TS, and Chao, JI* (2011) 7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel ROCK inhibitor blocks cytoskeleton function and cell migration. Biochemical Pharmacology, 81: 856-865. 

Liu, HF, Hu, HC, and Chao, JI* (2010) Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells. Chemico-Biological Interactions, 188: 535-545. 

Jiang, RH, Su, WC, Liu, HF, Huang, HS, and Chao, JI* (2010) Opposite expression of securin and gamma-H2AX regulates baicalein-induced cancer cell death. Journal of Cellular Biochemistry, 111: 274-283. 

Hsu, TS, Chen, C, Lee PT, Chiu, SJ, Liu, HF, and Chao, JI* (2008) 7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel synthetic compound  induces lung carcinoma cell death associated with inhibiting ERK and CDC2 phosphorylation via a p53-independent pathway. Cancer Chemotherapy and Pharmacology, 62: 799-808. 

Liu, HF, Hsiao, PW, and Chao, JI* (2008) Celecoxib induces p53-PUMA pathway for apoptosis in human colorectal cancer cells. Chemico-Biological Interactions, 176: 48-57. 

Chiu, SJ*, Chao, JI, Lin, YJ, and Hsu, TS (2008) Regulation of gamma-H2AX and securin contribute to apoptosis by oxaliplatin via a p38 mitogen-activated protein kinase -dependent pathway in human colorectal cancer cells. Toxicology Letters, 179: 63-70. 

Chiu, SJ, Hsu, TS, and Chao, JI* (2007) Expression of securin promotes colorectal cancer cell death via a p53-independent pathway after radiation. Chemico-Biological Interactions, 170: 153–161.

Chao, JI*, Su, WC, and Liu, HF (2007) Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT. Molecular Cancer Therapeutics, 6: 3039-3048. 

Hsiao, PW, Chang, CC, Liu, HF, Tsai, CM, Chiu, TH, and Chao, JI* (2007) Activation of p38 mitogen-activated protein kinase by celecoxib oppositely regulates survivin and gamma-H2AX in human colorectal cancer cells. Toxicology and Applied Pharmacology, 222: 97-104.

Chiu, SJ, Hsu, TS, and Chao, JI* (2006) Opposing securin and p53 protein expression in the oxaliplatin-induced cytotoxicity of human colorectal cancer cells. Toxicology Letters 167:122-130. 

Chao, JI*, Hsu, SH, and Tsou, TC (2006) Depletion of securin increases arsenite-induced chromosome instability and apoptosis via a p53-independent pathway. Toxicological Sciences 90: 73-86. 

Chao, JI* and Liu, HF (2006) The blockage of survivin and securin expression increases the cytochalasin B-induced cell death and growth inhibition in human cancer cells. Molecular Pharmacology 69: 154-164. 

Lin, J, Hsiao, PW, Chiu, TH, and Chao, JI* (2005) Combination of cyclooxygenase-2 inhibitors and oxaliplatin increases the cell death and growth inhibition in human colon cancer cells. Biochemical Pharmacology 70: 658–667. 

Kuo, PC, Liu, HF, and Chao, JI* (2004) Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. Journal of Biological Chemistry 279: 55875-55885. 

Chao, JI*, Kuo, PC, and Hsu TS (2004) Down-regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells. Journal of Biological Chemistry 279: 20267-20276.