Tacar Oktay, Indumathy Sivanjah, Tan Mei Lin, Baindur-Hudson Swati, Friedhuber Anna M, Dass Crispin R
College of Health and Biomedicine, Victoria University, Melbourne, Australia.
J Pharm Pharmacol. 2015 Feb;67(2):231-43. doi: 10.1111/jphp.12324. Epub 2014 Sep 11.
Doxorubicin (Dox) is a frontline chemotherapeutic against osteosarcoma (OS) that is plagued by side effects, particularly in the heart. The specific objective of this article is to investigate whether low-dose Dox treatment had pro-autophagic effects in cardiomyocytes as well as osteosarcoma cells.
This study characterises apoptotic (Bax) and autophagic (Beclin-1) biomarker levels in human OS and cardiomyocyte cell lines as well as in various tissues when mice are exposed to low (1 mg/kg, thrice weekly) and high (3 mg/kg thrice weekly) dose Dox for a month.
There was a decrease in Bax and increase in Beclin-1 in cardiac tissue in the high-dose group. Dox decreased Beclin-1 in the skin and liver, with no clear indication in the stomach, small intestine and testis. At low Dox doses of 10 and 100 nm in cardiomyocytes and OS cells, there is a pro-apoptotic effect, with a quicker response in the 100-nm condition, and a slower but steady increase of a pro-apoptotic response at the lower 10-nm dose. However, electron microscopy images revealed changes to human OS cells that resembled autophagy. Human prostate, breast and colorectal cells treated with 10-nm Dox showed ∼ 40% reduction in cell viability after 24 h.
In culture, cells of both cardiomyocytes and OS revealed a predominant pro-apoptotic response at the expense of autophagy, although both seemed to be occurring in vivo.
阿霉素（Dox）是治疗骨肉瘤（OS）的一线化疗药物，但存在副作用，尤其是对心脏的副作用。本文的具体目的是研究低剂量阿霉素治疗对心肌细胞和骨肉瘤细胞是否具有促自噬作用。
本研究对人骨肉瘤和心肌细胞系以及小鼠在接受低剂量（1mg/kg，每周三次）和高剂量（3mg/kg，每周三次）阿霉素治疗一个月后的各种组织中的凋亡（Bax）和自噬（Beclin-1）生物标志物水平进行了表征。
高剂量组心脏组织中Bax减少，Beclin-1增加。阿霉素使皮肤和肝脏中的Beclin-1减少，在胃、小肠和睾丸中无明显变化。在心肌细胞和骨肉瘤细胞中，低剂量10和100nm的阿霉素具有促凋亡作用，在100nm条件下反应更快，在较低的10nm剂量下促凋亡反应增加较慢但稳定。然而，电子显微镜图像显示人骨肉瘤细胞发生了类似自噬的变化。用10nm阿霉素处理的人前列腺、乳腺和结肠直肠细胞在24小时后细胞活力降低约40%。
在培养中，心肌细胞和骨肉瘤细胞均表现出以自噬为代价的主要促凋亡反应，尽管两者似乎都在体内发生。
