title: Promising pharmacological profile of a Kunitz-type inhibitor in murine renal cell carcinoma model.
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.
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.|Department of Biochemistry, Federal University of São Paulo, SP, Brazil.|CENTD- Center of Excellence in New Target Discovery, Butantan Institute, SP, Brazil.
authors: Jean Gabriel
authors: JG
authors: de Souza
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.|CENTD- Center of Excellence in New Target Discovery, Butantan Institute, SP, Brazil.
authors: Katia L.P.
authors: KL
authors: Morais
authors: INSERM UMR_S 1140-Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Eduardo
authors: E
authors: Anglés-Cano
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.|Department of Biochemistry, Federal University of São Paulo, SP, Brazil.
authors: Pamela
authors: P
authors: Boufleur
authors: Department of Pathology, University of Sao Paulo Medical School, SP, Brazil.
authors: Evandro Sobroza
authors: ES
authors: de Mello
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.
authors: Durvanei Augusto
authors: DA
authors: Maria
authors: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, SP, Brazil.
authors: Clarice Silvia Taemi
authors: CS
authors: Origassa
authors: Division of Urology, Arnaldo Vieira de Carvalho Cancer Institute, SP, Brazil.
authors: Hamilton
authors: H
authors: de Campos Zampolli
authors: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, SP, Brazil.|Nephrology Division, Federal University of São Paulo, SP, Brazil.
authors: Niels Olsen Saraiva
authors: NO
authors: Câmara
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.
authors: Carolina Maria
authors: CM
authors: Berra
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.
authors: Rosemary Viola
authors: RV
authors: Bosch
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, SP, Brazil.|CENTD- Center of Excellence in New Target Discovery, Butantan Institute, SP, Brazil.
authors: Ana Marisa
authors: AM
authors: Chudzinski-Tavassi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D060829:Arthropod Proteins; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012471:Salivary Proteins and Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C559369:Amblyomin-X protein, Amblyomma cajennense; D060829:Arthropod Proteins; C530105:Ccnd1 protein, mouse; D019394:Ki-67 Antigen; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; C052617:Bcl2 protein, mouse; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex
keywords: amblyomin-X; antitumor activity; renal cell carcinoma; tumor affinity; tumor resistance