Cell lines

DU-145 cell lines

Preparation Method

DU145 cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) (1μM) and incubated for 20 min at 37℃ protecting from light. After two washes in PBS (37℃), the cells were treated with 2.5 mg/ml of Cabozantinib(XL184).

Reaction Conditions

2.5 mg/ml, 48h

Applications

DU-145 cell lines expressed MET, and Cabozantinib(XL184) treatment had a cytostatic effect, blocking cells in G1 phase. Cabozantinib(XL184) induced an inhibition of the autophagic pathway in DU-145 cells, through an upregulation of the mTOR complex. This may be related to the high expression of the AXL that is observed in DU-145; this is also an RTK target for Cabozantinib(XL184).

Animal models

6- to 8-week-old NOD-SCID male mice

Dosage form

30 mg/kg/day, oral gavage

Applications

The expression of matrix metalloproteinase-1 (MMP-1), a crucial factor in cell migration, was markedly decreased in the cabozantinib(XL 184)-treated mice compared to in the vehicle group (P

Cabozantinib (XL184,BMS-907351) is a novel MET and VEGFR2 inhibitor that simultaneously inhibits metastasis, angiogenesis and tumor growth^[1]. Its IC50 values for VEGFR2 and c-Met are 0.035 nM and 1.3 nM^[2].

Cabozantinib(XL184) treatment of MAME cultures of MDA-MB-231 and HCC70 cells (HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths, even in cultures with HGF-expressing fibroblasts^[3]. The cellular stress induced by Cabozantinib resulted in the induction of ICD (a peculiar type of apoptosis) in DU-145 cell line^[4]. Cabozantinib has been reported to inhibit MMP-1 expression by blocking the HGF-MET signaling pathway in bladder cancer cells^[5]. MMP-1 was significantly decreased in ESCC cells treated with cabozantinib, which was the reason for the decreased migration activity of ESCC cells treated with cabozantinib^[6].

Cabozantinib inhibits tumor growth in a dose-dependent manner in human tumor models in rodents^[1]. In vivo pharmacodynamic studies showed substantial inhibition of RET in TT xenograft tumors following a single oral dose of cabozantinib^[7]. Cabozantinib showed excellent antitumor effects in vivo using CRC(colorectal cancer) explants model^[8].

References:
[1]. Yakes F Michael,Chen Jason, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.[J]. Molecular cancer therapeutics,2011,10(12).
[2]. Weon-Kyoo You, Barbara Sennino, et al. VEGF and c-Met Blockade Amplify Angiogenesis Inhibition in Pancreatic Islet Cancer[J]. Microenvironment and Immunology,2011.
[3]. Sameni Mansoureh,Tovar Elizabeth A, et al. Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models.[J]. Clinical cancer research : an official journal of the American Association for Cancer Research,2016,22(4).
[4] Scirocchi Fabio,Napoletano Chiara,et al. Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib[J]. Frontiers in Oncology,2021,11.
[5] Shintani T, Kusuhara Y, et al. The involvement of hepatocyte growth factor-MET-matrix metalloproteinase 1 signaling in bladder cancer invasiveness and proliferation. Effect of the MET inhibitor, cabozantinib (XL184), on bladder cancer cells. Urology. (2017) 101:169.e7-13. doi: 10.1016/j.urology.2016.12.006.
[6] Pei-Wen Yang, Yu-Cheng Liu, et al. Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC)[J]. Frontiers in Oncology, 2019.
[7] Bentzien Frauke,Zuzow Marcus, et al. In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer.[J]. Thyroid : official journal of the American Thyroid Association,2013,23(12).
[8] Scott Aaron J,Arcaroli John J,et al. Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms.[J]. Molecular cancer therapeutics,2018,17(10).