Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Antitumoral Effects of Dovitinib in Triple-Negative Breast Cancer are Synergized by Calcitriol in Vivo and In Vitro

Janice García-Quiroz
,
Nohemí Cárdenas-Ochoa
,
Rocío García-Becerra
,
Gabriela Morales-Guadarrama
ORCID logo ,
Edgar A. Méndez-Pérez
,
Clara Santos-Cuevas
,
Gerardo J. Ramírez-Nava
,
Mariana Segovia-Mendoza
,
Heriberto Prado-Garcia
ORCID logo ,
Euclides Avila
ORCID logo ,
Fernando Larrea
,
Lorenza Díaz
* ORCID logo
Version 1 : Received: 30 January 2021 / Approved: 1 February 2021 / Online: 1 February 2021 (17:29:30 CET)

A peer-reviewed article of this Preprint also exists.

García-Quiroz, J.; Cárdenas-Ochoa, N.; García-Becerra, R.; Morales-Guadarrama, G.; Méndez-Pérez, E.A.; Santos-Cuevas, C.; Ramírez-Nava, G.J.; Segovia-Mendoza, M.; Prado-García, H.; Avila, E.; et al. Antitumoral Effects of Dovitinib in Triple-Negative Breast Cancer Are Synergized by Calcitriol in Vivo and in Vitro. The Journal of Steroid Biochemistry and Molecular Biology 2021, 214, 105979, doi:10.1016/j.jsbmb.2021.105979. García-Quiroz, J.; Cárdenas-Ochoa, N.; García-Becerra, R.; Morales-Guadarrama, G.; Méndez-Pérez, E.A.; Santos-Cuevas, C.; Ramírez-Nava, G.J.; Segovia-Mendoza, M.; Prado-García, H.; Avila, E.; et al. Antitumoral Effects of Dovitinib in Triple-Negative Breast Cancer Are Synergized by Calcitriol in Vivo and in Vitro. The Journal of Steroid Biochemistry and Molecular Biology 2021, 214, 105979, doi:10.1016/j.jsbmb.2021.105979.

Abstract

Chemotherapy is a standard therapeutic option for triple-negative breast cancer (TNBC); however, its effectiveness is often compromised by drug-related toxicity and resistance development. Herein, we aimed to evaluate whether an improved antineoplastic effect could be achieved in vitro and in vivo in TNBC by combining dovitinib, a multi-kinase inhibitor, with calcitriol, a natural anti-cancer hormone. In vitro, cell proliferation and cell-cycle distribution were studied by sulforhodamine B-assays and flow cytometry. In vivo, dovitinib/calcitriol effects on tumor growth, angiogenesis and endothelium activation were evaluated in xenografted mice by caliper measures, Itgb3-immunohistochemistry and 99mTc-RGD2-tumor uptake. The drug combination elicited a synergistically improved antiproliferative effect in TNBC-derived cells, which allowed a 7-fold dovitinib dose-reduction. Mechanistically, the co-treatment induced cell death and accumulation in S and G2/M phases, while inhibited tumor growth to a greater extent than each compound alone. Tumor uptake of 99mTc-RGD2 was reduced by dovitinib, suggesting angiogenesis inhibition, which was corroborated by decreased endothelial cell growth and tumor vessel density. In summary, calcitriol synergized dovitinib anticancer effects in vitro and in vivo, allowing for a significant dose-reduction of dovitinib, while maintaining its antiproliferative potency. Our results suggest the beneficial convergence of independent antitumor mechanisms of dovitinib and calcitriol to inhibit TNBC-tumor growth.

Keywords

breast cancer; dovitinib; calcitriol; combination index; dose-reduction index; synergism.

Subject

Medicine and Pharmacology, Immunology and Allergy

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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