Institute of Pharmacology and Toxicology, Unit of Clinical Pharmacology, University of Veterinary Medicine, Vienna, Austria.
Institute of Pathology and Forensic Veterinary Medicine, University of Veterinary Medicine, Vienna, Austria.
Vet Comp Oncol. 2019 Dec;17(4):507-521. doi: 10.1111/vco.12514. Epub 2019 Jul 12.
Therapy of canine mammary tumours (CMTs) with classical antitumour drugs is problematic, so better therapeutic options are needed. Palbociclib (PD-0332991) is an innovative and effective anticancer drug for the treatment of breast cancer in women. Palbociclib is an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6, which are key regulators of the cell cycle machinery and thus cell proliferation. In the present in vitro study, we investigated whether Palbociclib also represents a candidate drug to combat CMT. For this purpose, the effect of Palbociclib was analysed in P114 and CF41 cells, two CMT cell lines with an endogenous CDK4/6 co-expression. Incubation of P114 and CF41 cells with Palbociclib resulted in a dose- and time-dependent loss of phosphorylated retinoblastoma protein (pRb), a classical CDK4/6 substrate within the cell cycle machinery. Moreover, treatment of CMT cells with Palbociclib-induced cell cycle arrest affected cell viability, prevented colony formation and impaired cell migration activity. Palbociclib also inhibited the growth of P114 and CF41 cell spheroids. Immunohistochemical analysis of canine patient samples revealed a consistent expression of CDK6 in different canine mammary carcinoma types, but an individual and tumour-specific expression pattern of phosphorylated pRb independent of the tumour grade. Together, our findings let us suggest that Palbociclib has antitumour effects on CMT cells and that canine patients may represent potential candidates for treatment with this CDK4/6 inhibitor.
用传统抗肿瘤药物治疗犬乳腺肿瘤（CMTs）存在问题，因此需要更好的治疗选择。帕博西尼（PD-0332991）是一种用于治疗女性乳腺癌的创新且有效的抗癌药物。帕博西尼是细胞周期蛋白依赖性激酶 4（CDK4）和 CDK6 的抑制剂，这两种酶是细胞周期机制的关键调节剂，因此也是细胞增殖的关键调节剂。在本体外研究中，我们研究了帕博西尼是否也可以作为治疗 CMT 的候选药物。为此，我们分析了 Palbociclib 对 P114 和 CF41 两种具有内源性 CDK4/6 共表达的 CMT 细胞系的作用。用 Palbociclib 孵育 P114 和 CF41 细胞，导致细胞周期机制中的经典 CDK4/6 底物磷酸化视网膜母细胞瘤蛋白（pRb）的剂量和时间依赖性丧失。此外，用 Palbociclib 处理 CMT 细胞会导致细胞周期停滞，从而影响细胞活力，阻止集落形成并损害细胞迁移活性。帕博西尼还抑制了 P114 和 CF41 细胞球的生长。对犬患者样本的免疫组织化学分析显示，不同犬乳腺癌类型中 CDK6 的表达一致，但磷酸化 pRb 的表达模式具有个体性和肿瘤特异性，与肿瘤分级无关。总之，我们的研究结果表明，帕博西尼对 CMT 细胞具有抗肿瘤作用，犬患者可能是这种 CDK4/6 抑制剂治疗的潜在候选者。
