Hwang Bor-Jang, Madabushi Amrita, Jin Jin, Lin Shiou-Yuh S, Lu A-Lien
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine Baltimore, MD 21201, USA.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine Baltimore, MD 21201, USA ; Current address: Department of Natural & Physical Sciences, Life Sciences Institute; Baltimore City Community College Baltimore, MD 21201.
Am J Cancer Res. 2014 May 26;4(3):211-21. eCollection 2014.
SIRT1, a member of the NAD(+)-dependent histone/protein deacetylase family, is involved in chromatin remodeling, DNA repair, and stress response and is a potential drug target. 5-fluorouracil (FU) and the SN1-type DNA methylating agent temozolomide (TMZ) are anticancer agents. In this study, we demonstrate that sirt1 knockout mouse embryonic fibroblast cells are more sensitive to FU and DNA methylating agents than normal cells. Based on these findings, the chemotherapy efficacy of SIRT1 inhibitors in combination with FU or TMZ were tested with human breast cancer cells. We found that treatments combining SIRT1 inhibitors with FU or TMZ show synergistic reduction of cell viability and colony formation of breast cancer cells. Thus, inhibition of SIRT1 activity provides a novel anticancer strategy.
SIRT1是NAD(+)依赖的组蛋白/蛋白质脱乙酰酶家族成员，参与染色质重塑、DNA修复和应激反应，是一个潜在的药物靶点。5-氟尿嘧啶（FU）和SN1型DNA甲基化剂替莫唑胺（TMZ）是抗癌药物。在本研究中，我们证明sirt1基因敲除的小鼠胚胎成纤维细胞比正常细胞对FU和DNA甲基化剂更敏感。基于这些发现，我们用人乳腺癌细胞测试了SIRT1抑制剂与FU或TMZ联合使用的化疗效果。我们发现，SIRT1抑制剂与FU或TMZ联合治疗可协同降低乳腺癌细胞的活力和集落形成。因此，抑制SIRT1活性提供了一种新的抗癌策略。
