Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma
2017
Authors:
Dragoj, MiodragMilošević, Zorica
Banković, Jasna
Tanić, Nikola
Pešić, Milica
Stanković, Tijana
Document Type:
Article (Published version)
,
© International Society for Cellular Oncology 2016
Metadata
Show full item recordAbstract:
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.
Keywords:
CXCR4; DOX; FAK; Invasion; Non-small cell lung carcinoma; ResistanceSource:
Cellular Oncology, 2017, 40, 1, 47-62Funding / projects:
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
DOI: 10.1007/s13402-016-0304-6
ISSN: 2211-3428
PubMed: 27822706
WoS: 000392318100004
Scopus: 2-s2.0-84994434560
URI
http://link.springer.com/10.1007/s13402-016-0304-6https://www.scopus.com/record/display.uri?eid=2-s2.0-84994434560&origin=SingleRecordEmailAlert&txGid=6CE299281CDB840158BFAC52EC5A2E1C.wsnAw8kcdt7IPYLO0V48gA:31
https://radar.ibiss.bg.ac.rs/handle/123456789/2540