Promising pharmacological profile of a Kunitz-type inhibitor in murine renal cell carcinoma model
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Jean Gabriel de Souza1,2,3, Katia L.P. Morais1,3, Eduardo Anglés-Cano4, Pamela Boufleur1,2, Evandro Sobroza de Mello5, Durvanei Augusto Maria1, Clarice Silvia Taemi Origassa6, Hamilton de Campos Zampolli7, Niels Olsen Saraiva Câmara6,8, Carolina Maria Berra1, Rosemary Viola Bosch1, Ana Marisa Chudzinski-Tavassi1,3
1Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil
2Department of Biochemistry, Federal University of São Paulo, SP, Brazil
3CENTD- Center of Excellence in New Target Discovery, Butantan Institute, SP, Brazil
4INSERM UMR_S 1140-Université Paris Descartes, Sorbonne Paris Cité, Paris, France
5Department of Pathology, University of Sao Paulo Medical School, SP, Brazil
6Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, SP, Brazil
7Division of Urology, Arnaldo Vieira de Carvalho Cancer Institute, SP, Brazil
8Nephrology Division, Federal University of São Paulo, SP, Brazil
Ana Marisa Chudzinski-Tavassi, email: [email protected]
Keywords: renal cell carcinoma, amblyomin-X, antitumor activity, tumor resistance, tumor affinity
Received: May 23, 2016 Accepted: August 13, 2016 Published: August 23, 2016
Renal cell carcinoma (RCC), also called kidney cancer or renal adenocarcinoma, is highly resistant to current treatments. It has been previously reported that a Kunitz-type inhibitor domain-containing protein, isolated from the salivary glands of the Amblyomma cajennense tick, triggers apoptosis in murine renal adenocarcinoma cells (Renca) by inhibiting the proteasome and endoplasmic reticulum stress. Of note, Amblyomin-X is the corresponding recombinant protein identified in the cDNA library from A. cajennense salivary glands. Herein, using orthotopic kidney tumors in mice, we demonstrate that Amblyomin-X is able to drastically reduce the incidence of lung metastases by inducing cell cycle arrest and apoptosis. The in vitro assays show that Amblyomin-X is capable of reducing the proliferation rate of Renca cells, promoting cell cycle arrest, and down-regulating the expression of crucial proteins (cyclin D1, Ki67 and Pgp) involved in the aggressiveness and resistance of RCC. Regarding non-tumor cells (NIH3T3), Amblyomin-X produced minor effects in the cyclin D1 levels. Interestingly, observing the image assays, the fluorescence-labelled Amblyomin-X was indeed detected in the tumor stroma whereas in healthy animals it was rapidly metabolized and excreted. Taken the findings together, Amblyomin-X can be considered as a potential anti-RCC drug candidate.
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