Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

BB-Cl-Amidine as a novel therapeutic for canine and feline mammary cancer via activation of the endoplasmic reticulum stress pathway

Authors: Melissa M. Ledet, Robyn Anderson, Rebecca Harman, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Gerlinde R. Van de Walle

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Mammary cancer is highly prevalent in dogs and cats and results in a poor prognosis due to critically lacking viable treatment options. Recent human and mouse studies have suggested that inhibiting peptidyl arginine deiminase enzymes (PAD) may be a novel breast cancer therapy. Based on the similarities between human breast cancer and mammary cancer in dogs and cats, we hypothesized that PAD inhibitors would also be an effective treatment for mammary cancer in these animals.

Methods

Canine and feline mammary cancer cell lines were treated with BB-Cl-Amidine (BB-CLA) and evaluated for viability and tumorigenicity. Endoplasmic reticulum stress was tested by western blot, immunofluorescence, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Canine and feline mammary cancer xenograft models were created using NOD scid gamma (NSG) mice, and were treated with BB-CLA for two weeks.

Results

We found that BB-CLA reduced viability and tumorigenicity of canine and feline mammary cancer cell lines in vitro. Additionally, we demonstrated that BB-CLA activates the endoplasmic reticulum stress pathway in these cells by downregulating 78 kDa Glucose-regulated Protein (GRP78), a potential target in breast cancer for molecular therapy, and upregulating the downstream target gene DNA Damage Inducible Transcript 3 (DDIT3). Finally, we established a mouse xenograft model of both canine and feline mammary cancer in which we preliminarily tested the effects of BB-CLA in vivo.

Conclusion

We propose that our established mouse xenograft models will be useful for the study of mammary cancer in dogs and cats, and furthermore, that BB-CLA has potential as a novel therapeutic for mammary cancer in these species.
Appendix
Available only for authorised users
Literature
1.
Hayes HM, Milne KL, Mandell CP. Epidemiological features of feline mammary carcinoma. Vet Rec. 1981;108:476–9.CrossRefPubMed
2.
MacEwen EG. Spontaneous tumors in dogs and cats: models for the study of cancer biology and treatment. Cancer Metastasis Rev. 1990;9:125–36.CrossRefPubMed
3.
Novosad CA. Principles of treatment for mammary gland tumors. Clin Tech Small Anim Pract. 2003;18:107–9.CrossRefPubMed
4.
Simon D, Knebel JW, Baumgartner W, Aufderheide M, Meyer-Lindenberg A, Nolte I. In vitro efficacy of chemotherapeutics as determined by 50% inhibitory concentrations in cell cultures of mammary gland tumors obtained from dogs. Am J Vet Res. 2001;62:1825–30.CrossRefPubMed
5.
Simon D, Schoenrock D, Baumgärtner W, Nolte I. Postoperative adjuvant treatment of invasive malignant mammary gland tumors in dogs with doxorubicin and docetaxel. J Vet Intern Med. 20:1184–90.
6.
Sorenmo KU, Harwood LP, King LG, Drobatz KJ. Case-control study to evaluate risk factors for the development of sepsis (neutropenia and fever) in dogs receiving chemotherapy. J Am Vet Med Assoc. 2010;236(6):650.CrossRefPubMed
7.
Vossenaar ER, Zendman AJW, van Venrooij WJ, Pruijn GJM. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays. 2003;25:1106–18.CrossRefPubMed
8.
Horibata S, Coonrod SA, Cherrington BD. Role for peptidylarginine deiminase enzymes in disease and female reproduction. J Reprod Dev. 2012;58:274–82.CrossRefPubMed
9.
Mohanan S, Cherrington BD, Horibata S, McElwee JL, Thompson PR, Coonrod SA, et al. Potential role of Peptidylarginine deiminase enzymes and protein Citrullination in Cancer pathogenesis. Biochem Res Int. 2012;2012:1–11.CrossRef
10.
McElwee JL, Mohanan S, Griffith OL, Breuer HC, Anguish LJ, Cherrington BD, et al. Identification of PADI2 as a potential breast cancer biomarker and therapeutic target. BMC Cancer. 2012;12:500.CrossRefPubMedPubMedCentral
11.
Cherrington BD, Mohanan S, Diep AN, Fleiss R, Sudilovsky D, Anguish LJ, et al. Comparative analysis of Peptidylarginine Deiminase-2 expression in canine, feline and human mammary Tumours. J Comp Pathol. 2012;147:139–46.CrossRefPubMed
12.
Chang X, Han J. Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog. 2006;45:183–96.CrossRefPubMed
13.
Chang X, Han J, Pang L, Zhao Y, Yang Y, Shen Z. Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer. 2009;9:40.CrossRefPubMedPubMedCentral
14.
Leth-Larsen R, Terp MG, Christensen AG, Elias D, Kühlwein T, Jensen ON, et al. Functional heterogeneity within the CD44 high human breast cancer stem cell-like compartment reveals a gene signature predictive of distant metastasis. Mol Med. 2012;18:1109–21.CrossRefPubMedPubMedCentral
15.
Wang Y, Li P, Wang S, Hu J, Chen XA, Wu J, et al. Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J Biol Chem. 2012;287(31):25941–53.CrossRefPubMedPubMedCentral
16.
Wang S, Chen XA, Hu J, Jiang J-K, Li Y, Yim K, et al. ATF4 gene network mediates cellular response to the anticancer PAD inhibitor YW3-56 in triple negative breast cancer cells. Mol Cancer Ther. 2015;14(4):877–88.CrossRefPubMedPubMedCentral
17.
Verfaillie T, Garg AD, Agostinis P, Schroder M, Kaufman RJ, Schroder M, et al. Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett. 2013;332:249–64.CrossRefPubMed
18.
Verfaillie T, Salazar M, Velasco G, Agostinis P, Verfaillie T, Salazar M, et al. Linking ER stress to autophagy: potential implications for cancer therapy. Int J Cell Biol. 2010;2010:1–19.CrossRef
19.
Wang M, Wey S, Zhang Y, Ye R, Lee AS. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal. 2009;11:2307–16.CrossRefPubMedPubMedCentral
20.
Harman RM, Curtis TM, Argyle DJ, Coonrod SA, Van de Walle GR. A comparative study on the in vitro effects of the DNA methyltransferase inhibitor 5-Azacytidine (5-AzaC) in breast/mammary cancer of different mammalian species. J Mammary Gland Biol Neoplasia. 2016;21:51–66.CrossRefPubMed
21.
Muth A, Subramanian V, Beaumont E, Nagar M, Kerry P, McEwan P, et al. Development of a selective inhibitor of protein arginine deiminase 2. J Med Chem. 2017;60:3198–211.CrossRefPubMed
22.
23.
Pesavento P, Liu H, Ossiboff RJ, Stucker KM, Heymer A, Millon L, et al. Characterization of a continuous feline mammary epithelial cell line susceptible to feline epitheliotropic viruses. Virol Methods. 2009;157(1):105–10.CrossRef
24.
Modiano JF, Kokai Y, Weiner DB, Pykett MJ, Nowell PC, Lyttle CR. Progesterone augments proliferation induced by epidermal growth factor in a feline mammary adenocarcinoma cell line. J Cell Biochem. 1991;45:196–206.CrossRefPubMed
25.
Knight JS, Subramanian V, O’Dell AA, Yalavarthi S, Zhao W, Smith CK, et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis. 2015;74:2199–206.CrossRefPubMed
26.
Horibata S, Vo TV, Subramanian V, Thompson PR, Coonrod SA. Utilization of the soft agar colony formation assay to identify inhibitors of tumorigenicity in breast cancer cells. J Vis Exp. 2015;99:e52727.
27.
Slade DJ, Subramanian V, Fuhrmann J, Thompson PR. Chemical and biological methods to detect post-translational modifications of arginine. Biopolymers. 2014;101:133–43.CrossRefPubMedPubMedCentral
28.
29.
Slack JL, Causey P, Thompson PR. Protein arginine deiminase 4: a target for an epigenetic cancer therapy. Cell Mol Life Sci. 2012;68(4):709–20.CrossRef
30.
Dong D, Ni M, Li J, Xiong S, Ye W, Virrey JJ, et al. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 2008;68:498–505.CrossRefPubMed
31.
Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11:381–9.CrossRefPubMed
32.
Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006;5:741–4.CrossRefPubMed
33.
Fernandez PM, Tabbara SO, Jacobs LK, Manning FCR, Tsangaris TN, Schwartz AM, et al. Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat. 2000;59:15–26.CrossRefPubMed
34.
Gentschev I, Ehrig K, Donat U, Hess M, Rudolph S, Chen N, et al. Significant growth inhibition of canine mammary carcinoma xenografts following treatment with oncolytic vaccinia virus GLV-1h68. J Oncol. 2010;2010:736907.CrossRefPubMedPubMedCentral
35.
Sonzogni-Desautels K, Knapp DW, Sartin E, Doré M. Effect of cyclooxygenase inhibitors in a xenograft model of canine mammary tumours. Vet Comp Oncol. 2011;9:161–71.CrossRefPubMed
36.
Michishita M, Ohtsuka A, Nakahira R, Tajima T, Nakagawa T, Sasaki N, et al. Anti-tumor effect of bevacizumab on a xenograft model of feline mammary carcinoma. J Vet Med Sci. 2016;78:685–9.CrossRefPubMed
37.
Kawalkowska J, Quirke A-M, Ghari F, Davis S, Subramanian V, Thompson PR, et al. Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses. Sci Rep. 2016;6:26430.CrossRefPubMedPubMedCentral
38.
Jones J, Causey C, Knuckley B, Slack-Noyes JL, Thompson PR. Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential. Curr Opin Drug Discov Devel. 2009;12(5):616–27.PubMedPubMedCentral
39.
Cherrington BD, Zhang X, McElwee JL, Morency E, Anguish LJ, Coonrod SA. Potential role for PAD2 in gene regulation in breast cancer cells. PLoS One. 2012;7:e41242.CrossRefPubMedPubMedCentral
40.
Li T, Su L, Lei Y, Liu X, Zhang Y, Liu X. DDIT3 and KAT2A proteins regulate TNFRSF10A and TNFRSF10B expression in endoplasmic reticulum stress-mediated apoptosis in human lung cancer cells. J Biol Chem. 2015;290:11108–18.CrossRefPubMedPubMedCentral
41.
Li B, Chen R, Chen L, Qiu P, Ai X, Huang E, et al. Effects of DDIT4 in methamphetamine-induced autophagy and apoptosis in dopaminergic neurons. Mol Neurobiol. 2016;54(3):1642–60.
42.
43.
Li G, Petiwala SM, Pierce DR, Nonn L, Johnson JJ. Selective modulation of endoplasmic reticulum stress markers in prostate cancer cells by a standardized mangosteen fruit extract. PLoS One. 2013;8:e81572.CrossRefPubMedPubMedCentral
44.
45.
Norval M, Maingay J, Else R. Studies of three canine mammary cell lines--II. In vivo properties. Eur J Cancer Clin Oncol. 1984;20:1501–8.CrossRefPubMed
46.
Killion J, Radinskey R, Fidler I. Orthotopic models are necessary to predict therapy of transplantable tumors in mice. Cancer Metastasis Rev. 1998-1999;17:279–84.CrossRefPubMed
47.
Troiani T, Schettino C, Martinelli E, Morgillo F, Tortora G, Ciardiello F. The use of xenograft models for the selection of cancer treatments with EGFR as an example. Crit Rev Oncol. 2008;65:200–11.CrossRef
48.
Stewart E, Shelat A, Bradley C, Chen X, Federico S, Thiagarajan S, et al. Development and characterization of a human orthotopic neuroblastoma xenograft. Dev Biol. 2015;407:344–55.CrossRefPubMedPubMedCentral
49.
Méchin M-C, Sebbag M, Arnaud J, Nachat R, Foulquier C, Adoue V, et al. Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseases. Int J Cosmet Sci. 2007;29:147–68.CrossRefPubMed
Metadata
Title
BB-Cl-Amidine as a novel therapeutic for canine and feline mammary cancer via activation of the endoplasmic reticulum stress pathway
Authors
Melissa M. Ledet
Robyn Anderson
Rebecca Harman
Aaron Muth
Paul R. Thompson
Scott A. Coonrod
Gerlinde R. Van de Walle
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4323-8

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Impact of the epidermal growth factor receptor mutation status on the prognosis of recurrent adenocarcinoma of the lung after curative surgery

Research article

Satisfactory results of a psychometric analysis and calculation of minimal clinically important differences of the World Health Organization quality of life-BREF questionnaire in an observational cohort study with lung cancer and mesothelioma patients

Research article

Mechanism of recipient cell-dependent differences in exosome uptake

Research article

Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer

Research article

Relationship between the extent of resection and the survival of patients with low-grade gliomas: a systematic review and meta-analysis

Research article

The role of vimentin in the tumor marker Nup88-dependent multinucleated phenotype
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits