title: Trastuzumab increases the sensitivity of HER2-amplified human gastric cancer cells to oxaliplatin and cisplatin by affecting the expression of telomere-associated proteins.
abstract: HER2amplification occurs in ~20% of gastric cancer (GC) cases; however, in gastric and gastroesophageal junction cancer withHER2gene amplification, trastuzumab in combination with cisplatin (DDP)-based chemotherapy has been reported to improve the oncological outcome. The aim of the present study was to evaluate the combined antitumor efficacy of trastuzumab and various platinum agents in GC cells and to elucidate mechanisms that may be involved in the interaction between trastuzumab and the platinum agents. Thein vitrochemosensitivity of the GC cells to platinum agents was evaluated using the CellTiter 96®AQueous One Solution Cell Proliferation Assay kit. Treatment with 1.0μg/ml trastuzumab for 48 h significantly increased the sensitivity of NCI-N87 cells withHER2amplification to oxaliplatin (Oxa) and DDP. This chemosensitivity was most prominent in the NCI-N87 cells, in which the half maximal inhibitory concentration of Oxa and DDP was decreased to ~3.29 and 6.91 times, respectively. The apoptotic effect of the platinum agents was evaluated by double-staining the GC cells with Annexin V-fluorescein isothiocyanate and propodium iodide. Consistent with the chemosensitivity analysis, apoptotic analysis indicated that trastuzumab significantly increased Oxa- and DDP-induced apoptosis in the NCI-N87 cells. Furthermore, the mRNA expression levels of various telomere-associated genes was determined by performing quantitative reverse transcription-polymerase chain reactions in a number of GC cell lines, and revealed that trastuzumab (alone and in combination with DDP) may downregulate the mRNA expression levels of theTPP1,TRF1,TRF2,TRF2IPandPOT1genes. However, western blot analysis demonstrated that trastuzumab (alone and in combination with DDP) may significantly downregulate the protein expression levels of telomeric repeat binding factor 2, protection of telomere 1 and TPP1 (formerly known as TINT1, PTOP and PIP). The results of the present study indicate a potential role of low-dose trastuzumab administration for increasing Oxa and DDP sensitivity inHER2-amplified GC cells, possibly via the downregulation of telomere-associated gene expression.
authors.affiliation: Clinical Oncology Laboratory, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China ; Department of Oncology Medicine, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Oncology Medicine, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Clinical Oncology Laboratory, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Qiufeng
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Clinical Oncology Laboratory, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Meizhen
authors.initials: M
authors.lastname: Wan
authors.affiliation: Clinical Oncology Laboratory, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Clinical Oncology Laboratory, Changzhou Tumor Hospital Affiliated to Suzhou University, Changzhou, Jiangsu 213002, P.R. China.
authors.forename: Changsong
authors.initials: C
authors.lastname: Zhang
keywords: gastric cancer; platinum; sensitivity; telomere-related protein; trastuzumab