Gefitinib (ZD1839) increases the efficacy of cisplatin in ovarian cancer cells

Ohta, Tsuyoshi; Ohmichi, Masahide; Shibuya, Tae; Takahashi, Toshifumi; Tsutsumi, Seiji; Takahashi, Kazuhiro; Kurachi, Hirohisa

doi:10.4161/cbt.19292

Cited by 20 publications

(15 citation statements)

References 33 publications

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“…31, 41, 42 Consistent with our data, several preclinical studies have demonstrated that Gefitinib suppresses ovarian cancer intra-abdominal dissemination or peritoneal metastasis in xenograft models, 43, 44, 45 indicating that cell-autonomous EGFR in ovarian cancer cells is critical for their metastatic colonization in peritoneum. Most of the clinical trials, however, showed limited or no clinical response of Gefitinib or Erlotinib in ovarian cancer patients.…”

Section: Discussionsupporting

confidence: 89%

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR

et al. 2017

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Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.

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Section: Discussionsupporting

confidence: 89%

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR

et al. 2017

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“…HER2 overexpression has been associated with a poor drug response in human ovarian cancer and a close relationship has been reported between HER2 and CDDP response in ovarian cancer cells (Lafky et al , 2008; Ohta et al , 2012; Cheng et al , 2013). The balance between cytostatic vs cytotoxic effects induced by CDDP in cancer cells is a consequence of DNA damage produced by CDDP-DNA adducts, which is in turn modulated by the interplay between tumour suppressors and oncogenic signalling controlling DNA synthesis, suppression of RNA transcription and effects on cell cycle, cell survival and death (Wang and Lippard, 2005).…”

Section: Discussionmentioning

confidence: 86%

Monitoring response to cytostatic cisplatin in a HER2(+) ovary cancer model by MRI and in vitro and in vivo MR spectroscopy

et al. 2013

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Background:Limited knowledge is available on alterations induced by cytostatic drugs on magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters of human cancers, in absence of apoptosis or cytotoxicity. We here investigated the effects of a cytostatic cisplatin (CDDP) treatment on 1H MRS and MRI of HER2-overexpressing epithelial ovarian cancer (EOC) cells and in vivo xenografts.Methods:High-resolution MRS analyses were performed on in vivo passaged SKOV3.ip cells and cell/tissue extracts (16.4 or 9.4 T). In vivo MRI/MRS quantitative analyses (4.7 T) were conducted on xenografts obtained by subcutaneous implantation of SKOV3.ip cells in SCID mice. The apparent diffusion coefficient (ADC) and metabolite levels were measured.Results:CDDP-induced cytostatic effects were associated with a metabolic shift of cancer cells towards accumulation of MRS-detected neutral lipids, whereas the total choline profile failed to be perturbed in both cultured cells and xenografts. In vivo MRI examinations showed delayed tumour growth in the CDDP-treated group, associated with early reduction of the ADC mean value.Conclusion:This study provides an integrated set of information on cancer metabolism and physiology for monitoring the response of an EOC model to a cytostatic chemotherapy, as a basis for improving the interpretation of non-invasive MR examinations of EOC patients.

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“…Gefitinib as single or combinative therapeutic agent has also been reported in clinical trials of breast cancer (Segovia-Mendoza et al , 2015), ovarian cancer (Posadas et al , 2007), pancreatic cancer (Brell et al , 2009), and cervical cancer (Goncalves et al , 2008). The mechanisms of action for gefitinib on these cancers include modulation of EGFR pathways such as PI3K/Akt, Raf1/Erk1/2, and cell cycle arrest (Zhou et al , 2009; Ohta et al , 2012; Segovia-Mendoza et al , 2015; Du et al , 2016). Therefore, gefitinib and LMB treatment may also be effective in treating these cancers with similar synergistic mechanisms as reported in our study.…”

Section: Discussionmentioning

confidence: 99%

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot. LMB displayed a synergistic effect on gefitinib- induced cytotoxicity in A549 (IC50: 25.0±2.1 μM of gefitinib+LMB vs. 32.0±2.5 μM of gefitinib alone, p<0.05). Gefitinib+LMB caused a significantly different cell cycle distribution and signaling pathways involving in EGFR/survivin/p21 compared with gefitinib. A549 cells then were treated with progressively increasing concentrations of gefitinib (A549GR) or in combination with LMB (A549GLR) over 10 months to generate gefitinib resistance. IC50 of gefitinib in A549GLR (37.0±2.8 μM) was significantly lower than that in A549GR (53.0±3.0 μM, p<0.05), which indicates that LMB could reverse gefitinib-induced resistance in A549. Further mechanism investigation revealed that the expression patterns of EGFR pathway and epithelial- mesenchymal transition (EMT) markers in A549, A549GR, and A549GLR were significantly different. In conclusion, LMB at a very low concentration combined with gefitinib showed synergistic therapeutic effects and ameliorated the development of gefitinib- induced resistance in lung cancer cells.

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Gefitinib (ZD1839) increases the efficacy of cisplatin in ovarian cancer cells

Cited by 20 publications

References 33 publications

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR

Monitoring response to cytostatic cisplatin in a HER2(+) ovary cancer model by MRI and in vitro and in vivo MR spectroscopy

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

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