Notarbartolo Monica, Poma Paola, Perri Daniela, Dusonchet Luisa, Cervello Melchiorre, D'Alessandro Natale
Dipartimento di Scienze Farmacologiche, Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy.
Cancer Lett. 2005 Jun 16;224(1):53-65. doi: 10.1016/j.canlet.2004.10.051.
The hepatic cancer HA22T/VGH cell line, which constitutively expresses activated nuclear factor-kappaB (NF-kB), was chosen as a model to examine the antitumor activity of curcumin, also in relationship to its possible influences on the activation of the transcription factor and on the expression of the inhibitory of apoptosis proteins (IAPs) and of other NF-kB target genes. Curcumin exerted cell growth inhibitory and apoptotic effects, related, at least part, to free radical generation and mainly dependent on caspase-9 and -3 activation. The combination of curcumin with cisplatin resulted in a synergistic antitumor activity and that with doxorubicin in additivity or sub-additivity. Curcumin exerted biphasic changes in the levels of NF-kB, with an increase at 8 h after its administration and a decrease at 16 h. For the combinations of curcumin with the other drugs, the levels of the transcription factor were lower than those predicted from the effects of the single agents, especially with a blunting of the remarkable increases in NF-kB activation induced by doxorubicin. Except for Bcl-2, the HA22T/VGH cells expressed different other genes, including the IAPs, implicated in cell proliferation and survival. Curcumin determined early changes in COX-2 and c-myc mRNAs, which were down-regulated, and in livin mRNA, which was up-regulated. Later it decreased Bcl-X(L) mRNA and increased Bcl-X(S) and c-IAP-2 mRNAs. Cisplatin and doxorubicin exerted distinct effects on gene expression. The cytotoxic interactions between curcumin and these agents were accompanied by synergistic (in particular with cisplatin) or additive effects of decrease in the expression of different genes, including c-myc, Bcl-X(L), c-IAP-2, NAIP and XIAP. However, the combinations attenuated also certain other influences on mRNA expression of the single agents, like, for example, the increases in Bcl-X(s) given by curcumin and doxorubicin. Overall, the effects of the drugs, alone or in combination, on tumor cell growth, cell death and gene expression did not show a simple relationship to the relative influences on NF-kB activation, inferring that they can be due also to other mechanisms.
肝癌HA22T/VGH细胞系持续表达活化的核因子-κB（NF-κB），该细胞系被选作模型来检测姜黄素的抗肿瘤活性，以及其对转录因子激活、凋亡抑制蛋白（IAPs）表达和其他NF-κB靶基因表达可能产生的影响。姜黄素发挥了细胞生长抑制和凋亡作用，至少部分与自由基生成有关，且主要依赖于半胱天冬酶-9和-3的激活。姜黄素与顺铂联合产生协同抗肿瘤活性，与阿霉素联合则产生相加或次相加作用。姜黄素使NF-κB水平发生双相变化，给药后8小时升高，16小时降低。对于姜黄素与其他药物的联合使用，转录因子水平低于单药作用的预测值，尤其是能减弱阿霉素诱导的NF-κB激活的显著升高。除Bcl-2外，HA22T/VGH细胞还表达其他不同基因，包括与细胞增殖和存活相关的IAPs。姜黄素导致COX-2和c-myc mRNA早期下调，livin mRNA上调。随后它降低了Bcl-X(L) mRNA水平，增加了Bcl-X(S)和c-IAP-2 mRNA水平。顺铂和阿霉素对基因表达有不同影响。姜黄素与这些药物之间的细胞毒性相互作用伴随着不同基因表达降低的协同（特别是与顺铂联合时）或相加作用，这些基因包括c-myc、Bcl-X(L)、c-IAP-2、NAIP和XIAP。然而，联合用药也减弱了单药对mRNA表达的某些其他影响，例如姜黄素和阿霉素引起的Bcl-X(s)升高。总体而言，这些药物单独或联合使用对肿瘤细胞生长、细胞死亡和基因表达的影响与对NF-κB激活的相对影响没有简单的关系，这表明它们也可能归因于其他机制。
