An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells

Yoshimi Iwaki; Stephanie E S Lindley; Noelle Bergman; Bruce F Smith; Satyanarayana R Pondugula

doi:10.3389/fvets.2024.1327377

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells

Front Vet Sci. 2024 Feb 13:11:1327377. doi: 10.3389/fvets.2024.1327377. eCollection 2024.

Authors

Yoshimi Iwaki^{1

2}, Stephanie E S Lindley¹, Noelle Bergman¹, Bruce F Smith³, Satyanarayana R Pondugula⁴

Affiliations

¹ Department of Clinical Science, College of Veterinary Medicine, Auburn University, Auburn, AL, United States.
² Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, United States.
³ Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States.
⁴ Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn, AL, United States.

Abstract

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells.

Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC₅, IC₁₀, IC₂₀, and IC₅₀ were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC₅, IC₁₀, IC₂₀, and IC₅₀ concentrations. After 72 hours, cell viability was assessed by CellTiter Glo.

Results and discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.

Keywords: chemotherapy; combination effect; dogs; osteosarcoma; zoledronate.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by the American College of Veterinary Internal Medicine Resident Research Grant and sponsored by the Purina Institute. This manuscript has not reviewed by ACVIM or the Purina Institute and do not necessarily reflect the views of the ACVIM, its officers, directors, or the Sponsor.