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Addition of vasopressin synthetic analogue [V4Q5]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models

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Abstract

[V4Q5]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V4Q5]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V4Q5]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V4Q5]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V4Q5]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V4Q5]dDAVP (0.3 μg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V4Q5]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V4Q5]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V4Q5]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V4Q5]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of the compound for the management of aggressive breast cancer.

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Abbreviations

[V4Q5]dDAVP:

1-deamino-4-valine-5-glutamine-8-d-arginine vasopressin

ANG:

Angiostatin

ANOVA:

Analysis of variance

AVP:

Arginine vasopressin

DAB:

3,3′-diaminobenzidine

dDAVP:

Desmopressin or 1-deamino-8-d-arginine vasopressin

D-MEM:

Dulbecco’s modified Eagle´s medium

EGFR:

Epidermal growth factor receptor

ER:

Oestrogen receptor

HER2/neu:

Human epidermal growth factor receptor 2

HRP:

Horseradish peroxidase

IC50 :

50 % inhibitory concentration

IHC:

Immunohistochemistry

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PKA:

cAMP-dependent protein kinase

PR:

Progesterone receptor

TNBC:

Triple negative breast cancer

V2r:

Vasopressin type 2 receptor

vWF:

Von Willebrand factor

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Acknowledgments

This work was supported by the National Agency for the Promotion of Science and Technology (ANPCYT, Argentina, grant Nº PICT2013/1772 to DFA), the National Institute of Cancer (grant Nº INC2012/INC2014 to DFA), the National University of Quilmes (grant Nº 53/1004 to DFA and DEG) and Chemo-Romikin. JG is a postdoctoral research fellow, MP is a doctoral research fellow, and DEG, GVR and DFA are members of the National Research Council (CONICET, Argentina). The authors gratefully acknowledge the work of Dr. Nancy B. Iannucci who passed away recently. Her untimely death was a profound loss to all of us. The authors would also like to acknowledge the generous assistance of Dr. Alejandra Scursoni in histopathological assessment.

Authors contributions

JG, GVR and DFA participated in the conception and design of this work. JG, MP, MBP and GVR developed the methodology. JG, MP, DEG, GVR and DFA were in charge of data acquisition and analysis. JG and DFA participated in the writing and revision of the manuscript. DFA supervised the study.

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Correspondence to Juan Garona.

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We acknowledge that DEG, GVR and DFA serve in a consultant/advisory role for Elea Laboratories S.A.C.I.F. y A. and Chemo-Romikin S.A. All other authors have no conflict of interests to declare.

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All animal protocols have been carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the U.S. National Institutes of Health and were approved by our institutional Animal Care Committee.

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Garona, J., Pifano, M., Pastrian, M.B. et al. Addition of vasopressin synthetic analogue [V4Q5]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models. Clin Exp Metastasis 33, 589–600 (2016). https://doi.org/10.1007/s10585-016-9799-5

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  • DOI: https://doi.org/10.1007/s10585-016-9799-5

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