Pang Siu-Kwong, Yu Chun-Wing, Guan Huaji, Au-Yeung Steve C F, Ho Yee-Ping
School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China.
Oncol Rep. 2008 Nov;20(5):1269-76.
Novel demethylcantharidin-platinum (DMC-Pt) complexes have been found to have superior in vitro anticancer activity against a number of human colon cancer cell lines when compared with oxaliplatin. One complex where the DMC-Pt moiety was integrated with trans-R,R-diamino-cyclohexane (DACH), exhibited the most pronounced cytotoxicity. To ascertain the mechanistic contribution of the DMC component, microarray analysis was conducted to compare the effect of the novel (R,R-DACH)-Pt-(DMC) complex and oxaliplatin, on the gene expression of human colorectal cancer (HCT116) cells. The Affymetrix HG-U133A oligonucleotide microarray was used, and the data allowed for the discrimination of genes that were specifically affected by the DMC ligand. One hundred and forty-one genes were found to be up-regulated. Of these, 48 can be classified according to different cellular responses including DNA repair, DNA synthesis, cell adhesion, cell cycle regulation, mitotic spindle checkpoint and apoptosis/antiapoptosis. The DMC ligand is likely to have caused damage to DNA bases and/or strands, and nucleotide mismatch, as highlighted by the recruitment of the repairing genes from the BER, HR and MMR. Antiapoptotic genes such as survivin, BRCA1 and ITGB3BP were up-regulated, and it is proposed that the inherent defense mechanism of the cell may have been triggered, creating potential resistance to apoptosis. This study is the first to demonstrate the impact of the DMC ligand on the gene expression profile of HCT116 colon cancer cells and further substantiates its inclusion in the design of novel platinum-based anticancer complexes.
与奥沙利铂相比，新型去甲基斑蝥素-铂（DMC-Pt）配合物已被发现对多种人类结肠癌细胞系具有优异的体外抗癌活性。其中一种DMC-Pt部分与反式-R,R-二氨基环己烷（DACH）整合的配合物表现出最显著的细胞毒性。为了确定DMC组分的作用机制，进行了微阵列分析，以比较新型（R,R-DACH）-Pt-（DMC）配合物和奥沙利铂对人结肠直肠癌（HCT116）细胞基因表达的影响。使用了Affymetrix HG-U133A寡核苷酸微阵列，该数据能够区分受DMC配体特异性影响的基因。发现有141个基因上调。其中，48个基因可根据不同的细胞反应进行分类，包括DNA修复、DNA合成、细胞黏附、细胞周期调控、有丝分裂纺锤体检查点和凋亡/抗凋亡。如BER、HR和MMR修复基因的募集所强调的，DMC配体可能对DNA碱基和/或链造成了损伤以及核苷酸错配。抗凋亡基因如生存素、BRCA1和ITGB3BP上调，有人提出细胞的固有防御机制可能已被触发，从而产生对凋亡的潜在抗性。本研究首次证明了DMC配体对HCT116结肠癌细胞基因表达谱的影响，并进一步证实了其在新型铂基抗癌配合物设计中的应用。
