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

• Published in: Journal of Veterinary Medical Science Vol. 86; no. 12; pp. 24-0344 - 1264
• Main Authors: LIU, Yishan, ELBADAWY, Mohamed, YAMAMOTO, Haru, AUGOMAA, Amira, ISHIHARA, Yusuke, KANEDA, Masahiro, USUI, Tatsuya, SASAKI, Kazuaki
• Format: Journal Article
• Language: English
• Published: Japan JAPANESE SOCIETY OF VETERINARY SCIENCE 2024; Japan Science and Technology Agency; The Japanese Society of Veterinary Science
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor activity; Apoptosis; Apoptosis - drug effects; Cancer; Caspase-3; Caspase-8; Caspase-9; Cat Diseases - drug therapy; Cats; cell apoptosis; Cell cycle; Cell proliferation; Cell Survival - drug effects; Cell viability; Cytotoxicity; Disease resistance; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Synergism; feline mammary tumor; Female; Genetics; Malignancy; Mammary gland; Mammary Neoplasms, Animal - drug therapy; Metastases; Mice; Organoids; Organoids - drug effects; pet adjuvant chemotherapy; Pharmacology; Polyether Polyketides; Pyrans - pharmacology; Pyrans - therapeutic use; Salinomycin; Tumors; Xenograft Model Antitumor Assays; cell apoptosis; feline mammary tumor; Salinomycin; organoids; pet adjuvant chemotherapy
• ISSN: 0916-7250; 1347-7439; 1347-7439
• DOI: 10.1292/jvms.24-0344

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.