A diverse induction of apoptosis by trabectedin in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cells
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2013
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Abstract
Trabectedin (Yondelis, ET-743), a semi synthetic tetrahydroisoquinoline alkaloid that was originally derived from the marine tunicate Ecteinascidia turbinata. The objective of this study was to investigate whether trabectedin mediated apoptosis shows any diversity in human breast cancer cell lines with different genotypes. Trabectedin induced cytotoxicity and apoptosis in both breast cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD were significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by trabectedin treatment in MCF-7 cells. However, in MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions were induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 4.8- and 5.2-fold in MDA-MB-453 cells. Moreover, trabectedin treatment increased the generation of ROS in both breast cancer cells. We have shown that trabectedin causes selective activation of extrinsic and intrinsic apoptotic pathways in two genotypically different breast cancer cells. This preliminary data might guide clinicians to choose appropriate combination agents with trabectedin based on different molecular subtypes of breast cancer. © 2013 Elsevier Ireland Ltd.
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Apoptosis , bcl-2-Associated X Protein , bcl-Associated Death Protein , Breast Neoplasms , Caspase 3 , Caspase 7 , Cell Line, Tumor , Cytochromes c , Dioxoles , Female , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins , MCF-7 Cells , Mitochondria , Mitochondrial Proteins , Reactive Oxygen Species , Receptors, TNF-Related Apoptosis-Inducing Ligand , Tetrahydroisoquinolines , caspase 3 , cytochrome c , death receptor , epidermal growth factor receptor 2 , estrogen receptor , protein Bax , protein bcl xl , reactive oxygen metabolite , trabectedin , tumor necrosis factor related apoptosis inducing ligand , 1,3 dioxolane derivative , BAD protein, human , BAX protein, human , CASP3 protein, human , CASP7 protein, human , caspase 3 , caspase 7 , cytochrome c , DIABLO protein, human , mitochondrial protein , protein BAD , protein Bax , reactive oxygen metabolite , signal peptide , tetrahydroisoquinoline derivative , TNFRSF10A protein, human , trabectedin , tumor necrosis factor related apoptosis inducing ligand receptor , antineoplastic activity , apoptosis , article , breast cancer , cell strain MCF 7 , concentration (parameters) , controlled study , cytotoxicity , Ecteinascidia turbinata , enzyme metabolism , genotype , human , human cell , mitochondrion , priority journal , protein expression , protein folding , Urochordata , apoptosis , breast tumor , drug effects , female , gene expression regulation , genetics , MCF 7 cell line , metabolism , pathology , tumor cell line