David, M., Ribeiro, J., Descotes, F. et al. (5 more authors) (2012) Targeting lysophosphatidic acid receptor type 1 with Debio 0719 inhibits spontaneous metastasis dissemination of breast cancer cells independently of cell proliferation and angiogenesis. International Journal of Oncology, 40 (4). pp. 1133-1141. ISSN 1019-6439
Abstract
Metastasis is the main cause of death for cancer patients. Targeting factors that control metastasis formation is a major challenge for clinicians. Lysophosphatidic acid (LPA) is a bioactive phospholipid involved in cancer. LPA activates at least six independent G protein-coupled receptors (LPA1-6). Tumor cells frequently co-express multiple LPA receptors, puzzling the contribution of each one to cancer progression. All three receptors, LPA1, LPA2 and LPA3, act as oncogenes and prometastatic factors in the mouse mammary gland. The competitive inhibitor of LPA1 and LPA3 receptors, Ki16425, inhibits efficiently breast cancer bone metastases in animal models. We showed here that Debio 0719, which corresponds to the R-stereoisomer of Ki16425 exhibited highest antagonist activities at LPA1 (IC50=60 nM) and LPA3 (IC50=660 nM) than Ki16425 [IC50=130 nM (LPA1); IC50=2.3 µM (LPA3)]. In vitro, Debio 0719, inhibited LPA-dependent invasion of the 4T1 mouse mammary cancer cells. In vivo, early but not late administration of Debio 0719 (50 mg/kg p.o. twice daily) to BALB/c mice during the course of orthotopic 4T1 primary tumor growth reduced the number of spontaneously disseminated tumor cells to bone and lungs without affecting the growth of primary tumors and tumor-induced angiogenesis. We found that increased LPA1 mRNA expression in primary tumors of breast cancer patients correlated significantly with their positive lymph node status (p<0.001). Altogether, our results suggest that LPA1 controls early events of metastasis independently of cell proliferation and angiogenesis. Therefore, targeting this receptor with Debio 0719 has a high therapeutic potential against metastasis formation for breast cancer patients.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2011 Spandidos Publications. Reproduced in accordance with the publisher's self-archiving policy. |
Keywords: | Animals; Breast Neoplasms; Calcium; Cell Growth Processes; Cell Line, Tumor; Female; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; RNA, Messenger; Receptors, Lysophosphatidic Acid; Signal Transduction |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 19 Nov 2019 16:06 |
Last Modified: | 20 Nov 2019 15:15 |
Status: | Published |
Publisher: | Spandidos Publications |
Refereed: | Yes |
Identification Number: | 10.3892/ijo.2011.1309 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:152906 |