Promising pharmacological profile of a Kunitz-type inhibitor in murine renal cell carcinoma model

Promising pharmacological profile of a Kunitz-type inhibitor in murine renal cell carcinoma model

Author de Souza, Jean Gabriel Autor UNIFESP Google Scholar
Morais, Katia L. P. Google Scholar
Angles-Cano, Eduardo Google Scholar
Boufleur, Pamela Autor UNIFESP Google Scholar
de Mello, Evandro Sobroza Google Scholar
Maria, Durvanei Augusto Google Scholar
Taemi Origassa, Clarice Silvia Google Scholar
Zampolli, Hamilton de Campos Google Scholar
Saraiva Camara Autor UNIFESP Google Scholar
Berra, Carolina Maria Google Scholar
Bosch, Rosemary Viola Google Scholar
Chudzinski-Tavassi, Ana Marisa Google Scholar
Abstract 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.
Keywords renal cell carcinoma
amblyomin-X
antitumor activity
tumor resistance
tumor affinity
Language English
Sponsor Sao Paulo Research Foundation
BNDES
National Council of Technological and Scientific Development [CNPq]
Coordination of Improvement of Higher Education Personnel (CAPES)
Grant number FAPESP: 2010/52669-3
FAPESP: 2010/07958-7
FAPESP: 2012/06944-8
FAPESP: 2012/02270-2
FAPESP: CENTD 2015/50040-4
FAPESP: CeTICs 2013/07467-1
BNDES: 13.2.0711.1/2013
CNPq: 305445/2013-8
Date 2016
Published in Oncotarget. Albany, v. 7, n. 38, p. 62255-62266, 2016.
ISSN 1949-2553 (Sherpa/Romeo, impact factor)
Publisher Impact Journals Llc
Extent 62255-62266
Origin http://dx.doi.org/10.18632/oncotarget.11555
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000387164700108
URI http://repositorio.unifesp.br/handle/11600/50962

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