Shishodia Shishir, Amin Hesham M, Lai Raymond, Aggarwal Bharat B
Cytokine Research Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Biochem Pharmacol. 2005 Sep 1;70(5):700-13. doi: 10.1016/j.bcp.2005.04.043.
Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin's lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL's resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappaB and IkappaB kinase and phosphorylated forms of IkappaBalpha and p65. This correlated with expression of TNF, IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappaB and inhibited the consitutively active IkappaBalpha kinase (IKK), and phosphorylation of IkappaBalpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappaB-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PARP cleavage, and annexin V staining. That NF-kappaB activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappaB complex and inhibited the proliferation of MCL cells. Constitutive NF-kappaB activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappaB activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappaB and IKK leading to suppression of expression of NF-kappaB-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL.
人套细胞淋巴瘤（MCL）是一种侵袭性B细胞非霍奇金淋巴瘤，其特征在于细胞周期蛋白D1的过表达，该蛋白在MCL的存活和增殖中起重要作用。由于MCL对当前化疗具有抗性，因此需要新的治疗方法。已知MCL细胞过表达NF-κB调节的基因产物（包括细胞周期蛋白D1），我们使用姜黄素（一种药理安全性良好的药物）在多种MCL细胞系中靶向NF-κB。所检测的所有四种MCL细胞系均有细胞周期蛋白D1的过表达、组成型活性NF-κB和IκB激酶以及IκBα和p65的磷酸化形式。这与TNF、IκBα、Bcl-2、Bcl-xl、COX-2和IL-6的表达相关，这些均受NF-κB调节。然而，在用姜黄素处理细胞后，组成型活性NF-κB被下调，组成型活性IκBα激酶（IKK）受到抑制，IκBα和p65的磷酸化也受到抑制。姜黄素还抑制了IKK激活所需的Akt的组成型激活。因此，所有NF-κB调节的基因产物的表达均被这种多酚下调，导致增殖受到抑制、细胞周期停滞在细胞周期的G1/S期，并如半胱天冬酶激活、PARP裂解和膜联蛋白V染色所示诱导细胞凋亡。从IKK/NEMO结合域和p65衍生的肽抑制组成型活性NF-κB复合物并抑制MCL细胞增殖这一观察结果也表明，NF-κB激活与细胞增殖直接相关。发现组成型NF-κB激活是由TNF引起的，因为抗TNF抗体同时抑制NF-κB激活和细胞增殖。总体而言，我们的结果表明，姜黄素抑制组成型NF-κB和IKK，导致NF-κB调节的基因产物表达受到抑制，从而导致MCL中增殖受到抑制、细胞周期停滞和细胞凋亡诱导。
