High drug efflux pump capacity and low DNA damage response induce doxorubicin resistance in canine hemangiosarcoma cell lines
High drug efflux pump capacity and low DNA damage response induce doxorubicin resistance in canine hemangiosarcoma cell lines
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DOI：
10.1016/j.rvsc.2019.09.011
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发表时间：
2019-12-01
影响因子：
2.4
通讯作者：
Kimura, Takashi
中科院分区：
文献类型：
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作者：
Morita, Atsuya;Aoshima, Keisuke;Kimura, Takashi
犬血管肉瘤（Canine hemangiosarcoma， HSA）是犬的一种侵袭性恶性内皮肿瘤，由于其高侵袭性、高转移潜力和对抗癌药物的反应性差，预后较差。虽然以阿霉素为基础的化疗经常在手术治疗后进行，但其对生存率的影响有限。获得耐药性是造成这一问题的原因之一，但其潜在机制尚不清楚。在本研究中，我们旨在通过建立耐多柔比星（DR） HSA细胞系来确定犬HSA的耐药机制。HSA细胞系暴露于浓度逐渐增加的阿霉素中。当细胞能够在比初始培养高16倍的阿霉素浓度下生长时，它们被指定为DR-HSA细胞系。这些DR-HSA细胞系的特性表明，与亲本细胞系相比，这些细胞系具有更高的药物外排泵能力。此外，DR-HSA细胞系尽管携带高DNA损伤负荷，但没有表现出DNA损伤反应的激活，这意味着细胞凋亡没有被强烈诱导。总之，犬HSA细胞株通过增加药物外排泵能力和降低DNA损伤反应获得阿霉素耐药。本研究为进一步研究犬HSA耐药机制提供了有益的结果。
Canine hemangiosarcoma (HSA) is an aggressive malignant endothelial tumor in dogs and characterized by poor prognosis because of its high invasiveness, high metastatic potential, and poor responsiveness to anti-cancer drugs. Although doxorubicin-based chemotherapy is regularly conducted after surgical treatment, its effects on survival rates are limited. Acquisition of drug resistance is one of the causes of this problem, but the underlying mechanisms remain unclear. In the present study, we aimed to identify the drug-resistance mechanism in canine HSA by establishing doxorubicin-resistant (DR) HSA cell lines. HSA cell lines were exposed to doxorubicin at gradually increasing concentrations. When the cells were able to grow in the presence of a 16-fold higher doxorubicin concentration compared with the initial culture, they were designated DR-HSA cell lines. Characterization of these DR-HSA cell lines revealed higher drug efflux pump capacity compared with the parental cell lines. Furthermore, the DR-HSA cell lines did not show activation of the DNA damage response despite carrying high DNA damage burdens, meaning that apoptosis was not strongly induced. In conclusion, canine HSA cell lines acquired doxorubicin resistance by increasing their drug efflux pump capacity and decreasing the DNA damage response. This study provides useful findings to promote further research on the drug-resistance mechanisms in canine HSA.