title: A diverse induction of apoptosis by trabectedin in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cells.
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.
authors.affiliation: Section of Molecular Biology, Department of Biology, Faculty of Science and Letters, Celal Bayar University, 45140 Muradiye, Manisa, Turkey. Electronic address: harika.atmaca@cbu.edu.tr.
authors.forename: Harika
authors.initials: H
authors.lastname: Atmaca
authors.affiliation: Section of Molecular Biology, Department of Biology, Faculty of Science and Letters, Celal Bayar University, 45140 Muradiye, Manisa, Turkey.
authors.forename: Emir
authors.initials: E
authors.lastname: Bozkurt
authors.affiliation: Section of Molecular Biology, Department of Biology, Faculty of Science and Letters, Celal Bayar University, 45140 Muradiye, Manisa, Turkey.
authors.forename: Selim
authors.initials: S
authors.lastname: Uzunoglu
authors.affiliation: Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, 35100 Bornova, Izmir, Turkey.
authors.forename: Ruchan
authors.initials: R
authors.lastname: Uslu
authors.affiliation: Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, 35100 Bornova, Izmir, Turkey.
authors.forename: Burcak
authors.initials: B
authors.lastname: Karaca
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C494826:BAX protein, human; C412403:DIABLO protein, human; D004149:Dioxoles; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D044005:Tetrahydroisoquinolines; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D000077606:Trabectedin
keywords: Apoptosis; Breast cancer; MCF-7; MDA-MB-453; Reactive oxygen species; Trabectedin (Yondelis, ET-743)