In?vitro and in?vivo therapeutic efficacy of CXCR4 antagonist BKT140 against human non-small cell lung cancer

详细信息    查看全文

• 作者：Duha Fahham ; MSc^a ; Ido D. Weiss ; PhD^a ; Michal Abraham ; PhD^a ; ^b ; Katia Beider ; PhD^a ; Wald Hanna^a ; Zippora Shlomai ; MSc^c ; Orly Eizenberg ; PhD^b ; Gideon Zamir ; MD^c ; Uzi Izhar ; MD^d ; Oz M. Shapira ; MD^d ; Amnon Peled ; PhD^a ; Ori Wald ; MD ; PhD^a ; ^d ; ^{ori.wald@mail.huji.ac.il}
• 关键词：9 ; 10
• 刊名：The Journal of Thoracic and Cardiovascular Surgery
• 出版年：2012
• 出版时间：November, 2012
• 年：2012
• 卷：144
• 期：5
• 页码：1167-1175.e1
• 全文大小：1260 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferencesml version=""1.0"" encoding=""UTF-8""?>

Objectives

CXCR4/CXCL12 interactions promote non-small cell lung cancer (NSCLC) growth and dissemination. Furthermore, this axis might promote NSCLC resistance to chemotherapy and/or radiotherapy. Therefore, the CXCR4/CXCL12 axis constitutes an attractive therapeutic target for the treatment of NSCLC. We aimed to characterize the therapeutic efficacy of the novel CXCR4 antagonist BKT140 against human NSCLC.

Methods

We determined the CXCR4 expression in 5 NSCLC cell lines (H358, A549, H460, H1299, and L4). We then tested the colony-forming capacity and proliferation of these cells in the presence of CXCL12 and BKT140. Next, we measured the in?vivo growth of A549 and H460 xenografts with or without BKT140 treatment. Finally, we examined, in?vitro, the potential antiproliferative effect of BKT140 combined with cisplatin or paclitaxel and after irradiation of NSCLC cells.

Results

All tested cell lines expressed CXCR4 and showed increased colony formation in response to CXCL12 stimulation. BKT140 reduced the colony-forming capacity of NSCLC cells. Proliferation assays demonstrated both cytotoxic and cytostatic properties for this peptide. H460 cells were the most sensitive to BKT140 and A549 cells the least. Subcutaneous administration of BKT140 significantly delayed the development of H460 xenografts and showed a similar trend for A549 xenografts. Finally, the antiproliferative effects of BKT140 appears to be additive to those of chemotherapeutic drugs and radiotherapy.

Conclusions

Targeting the CXCL12/CXCR4 axis with BKT140 attenuated NSCLC cells tumor growth and augmented the effects of chemotherapy and radiotherapy. Future research will benefit from delineating the downstream mechanism of BKT140 action and defining BKT140 susceptibility markers.