TAILIEUCHUNG - Báo cáo khoa học: The novel molecule 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]4-(2-chloroethyl)-phenyl acetate inhibits phosphoinositide 3-kinase⁄Akt⁄mammalian target of rapamycin signalling through JNK activation in cancer cells

Screening a compound library of compound 48⁄80 analogues, we identified 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate (E1) as a novel inhibitor of the phosphoinositide 3-kinase⁄Akt pathway. In order to determine the mechanism of action of E1, we analysed the effect of E1 on components of the phosphoinositide 3-kinase⁄Akt⁄mammalian target of rapamycin (mTOR) pathway. | ỊFEBS Journal The novel molecule 2- 5- 2-chloroethyl -2-acetoxy-benzyl -4- 2-chloroethyl -phenyl acetate inhibits phosphoinositide 3-kinase Akt mammalian target of rapamycin signalling through JNK activation in cancer cells Ka-Kei Ho1 Evelyn Rosivatz2 Richard M. Gunn3 4 Mark E. B. Smith3 Alexandra V. Stavropoulou1 Erika Rosivatz2 Macba G. Numbere3 John B. Wong3 Valerie G. H. Lafitte3 Jonathan M. Behrendt3 Stephen S. Myatt1 Helen C. Hailes3 Rudiger Woscholski2 4 and Eric . Lam1 4 1 Cancer Research UK Labs Department of Oncology Imperial college London Hammersmith Hospital UK 2 Division of Celland Molecular Biology ImperialCollege London UK 3 Department of Chemistry University College London UK 4 ChemicalBiology Centre ImperialCollege London UK Keywords Akt cancer cells JNK PI3K small molecules Correspondence E. . Lam Cancer Research UK Labs Department of Oncology ImperialCollege London Hammersmith Hospital UK Fax 44 20 8383 5830 Tel 44 20 8383 5829 E-mail Received 8 January 2009 revised 7 April 2009 accepted 22 May 2009 doi Screening a compound library of compound 48 80 analogues we identified 2- 5- 2-chloroethyl -2-acetoxy-benzyl -4- 2-chloroethyl -phenyl acetate E1 as a novel inhibitor of the phosphoinositide 3-kinase Akt pathway. In order to determine the mechanism of action of E1 we analysed the effect of E1 on components of the phosphoinositide 3-kinase Akt mammalian target of rapamycin mTOR pathway. E1 demonstrated dose-dependent and time-dependent repression of Akt and mTOR activity in prostate and breast cancer cell lines PC-3 and MCF-7 respectively. Inhibition of Akt and mTOR activity by E1 also coincided with increased c-Jun NH2-terminal kinase JNK phosphorylation. However the mode of action of E1 is different from that of the mTOR inhibitor rapamycin. Proliferation and cell cycle analysis revealed that E1 induced cell cycle arrest and cell death in PC-3 and MCF-7 cells. Moreover pretreatment

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