Salinomycin induces apoptosis and potentiates the antitumor effect of doxorubicin against feline mammary tumor 2.5D organoids

Abstract

Feline mammary tumors (FMT) are the third most common form of neoplasm in cats. The prognosis of FMT is poor due to its high malignancy and metastatic potential. The outcomes of treatment using the common anticancer drug doxorubicin (DOX) are unsatisfactory, with resistance inevitably leading to treatment failure and disease recurrence. Salinomycin (SAL), an antibiotic, has been reported to exert anticancer effects on both human and canine mammary tumors. To recapitulate the genetic and molecular imprints of the original tumor sample, we generated four strains of patient-derived FMT 2.5D organoids (FMTO) to examine the anti-tumor potential of SAL. Our results revealed that SAL decreased cell viability in a dose-dependent manner. Treatment of FMTO with SAL-induced cell apoptosis, represented by an upregulation of P21, Caspase-8, and Caspase-9, and increased activity of Caspase-3/7. The combination of low-dose SAL with DOX (SD) potentiated the cytotoxicity of the latter in both DOX-resistant and DOX-sensitive strains, promoting cell apoptosis and cell-cycle arrest. In vivo, experiments using FMTO-derived xenografts engrafted into mice revealed decreased tumor growth following SAL administration. In conclusion, SAL showed anticancer activity against FMTO and potentiated the anticancer effect of DOX by inhibiting cell proliferation and inducing apoptosis and cell cycle arrest. These results suggest that SAL may represent a new adjuvant treatment option for patients with FMT.