Miodrag Dragoj1, Zorica Milosevic1, Jasna Bankovic1, Nikola Tanic1, Milica Pesic1, Tijana Stankovic2. 1. Institute for Biological Research "Sinisa Stankovic", Department of Neurobiology, University of Belgrade, Despota Stefana 142, Belgrade, 11060, Serbia. 2. Institute for Biological Research "Sinisa Stankovic", Department of Neurobiology, University of Belgrade, Despota Stefana 142, Belgrade, 11060, Serbia. tijana.andjelkovic@ibiss.bg.ac.rs.
Abstract
BACKGROUND: Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells. METHODS: qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment. RESULTS: We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G2/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion. CONCLUSIONS: From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.
BACKGROUND: Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells. METHODS: qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLCpatients and the humanNSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment. RESULTS: We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G2/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion. CONCLUSIONS: From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.
Authors: Hong-Fei Ji; Da Pang; Song-Bin Fu; Yan Jin; Lei Yao; Ji-Ping Qi; Jing Bai Journal: J Cancer Res Clin Oncol Date: 2012-11-11 Impact factor: 4.553
Authors: Amrita Datta; Nobel Bhasin; Hogyoung Kim; Manish Ranjan; Barbara Rider; Zakaria Y Abd Elmageed; Debasis Mondal; Krishna C Agrawal; Asim B Abdel-Mageed Journal: Cancer Lett Date: 2015-03-18 Impact factor: 8.679
Authors: Vita M Golubovskaya; Brittany Sumbler; Baotran Ho; Michael Yemma; William G Cance Journal: Anticancer Agents Med Chem Date: 2014-01 Impact factor: 2.505
Authors: E Ota; Y Abe; Y Oshika; Y Ozeki; M Iwasaki; H Inoue; H Yamazaki; Y Ueyama; K Takagi; T Ogata Journal: Br J Cancer Date: 1995-09 Impact factor: 7.640
Authors: Muhamad Mustafa; Amer Ali Abd El-Hafeez; Dalia A Abdelhafeez; Dalia Abdelhamid; Yaser A Mostafa; Pradipta Ghosh; Alaa M Hayallah; Gamal El-Din A Abuo-Rahma Journal: Future Med Chem Date: 2021-08-03 Impact factor: 4.767