Carlson A, Alderete K S, Grant M K O, Seelig D M, Sharkey L C, Zordoky B N M
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
Vet Comp Oncol. 2018 Jun;16(2):253-261. doi: 10.1111/vco.12375. Epub 2017 Dec 13.
Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti-proliferative and/or pro-apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD-1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth-inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro-apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation.
血管肉瘤（HSA）是一种具有侵袭性生物学行为的高度恶性肿瘤。与其他家畜相比，HSA在犬类中更为常见。即使接受化疗和手术，患有HSA的犬类的中位生存时间仍然很短。因此，迫切需要改进辅助化疗方案，以改善患有HSA的犬类的临床结局。白藜芦醇已被证明在人类癌细胞系中具有强大的抗增殖和/或促凋亡特性。然而，白藜芦醇在犬类HSA中的潜在抗癌作用尚未见报道。本研究的目的是确定白藜芦醇单独使用或与常用化疗药物阿霉素联合使用时对HSA细胞的生长抑制作用。用不同浓度的白藜芦醇处理青蛙和DD-1犬HSA细胞系，同时添加或不添加阿霉素。通过MTT法测定细胞活力。通过蛋白质印迹法评估凋亡蛋白的表达、p38丝裂原活化蛋白激酶（MAPK）、AMP活化蛋白激酶（AMPK）和细胞外信号调节激酶1/2（ERK1/2）的激活情况。与人类癌细胞系相似，白藜芦醇显著抑制了两种HSA细胞系的生长并诱导了凋亡。从机制上讲，白藜芦醇激活了p38 MAPK，但不影响AMPK或ERK1/2信号通路。进一步的实验表明，白藜芦醇增强了阿霉素对两种HSA细胞系的生长抑制和凋亡作用。这些发现表明白藜芦醇在犬类HSA细胞中具有促凋亡作用；因此，将其用作犬类HSA患者的潜在辅助治疗值得进一步研究。
