The natural flavonoid apigenin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy
The natural flavonoid apigenin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy
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DOI：
10.1016/j.biopha.2017.01.056
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发表时间：
2017-04-01
影响因子：
7.5
通讯作者：
Erdogan, Zeynep
中科院分区：
文献类型：
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作者：
Erdogan, Suat;Turkekul, Kader;Erdogan, Zeynep
前列腺癌（PCa）是第二种最常见的癌症，也是男性癌症相关死亡的第五大原因。化疗耐药性的产生、肿瘤复发和转移仍然是有效治疗的主要障碍，并且所有这些都被确定与癌症干细胞（CSC）相关。天然类黄酮如芹菜素已被证明具有通过CSC致敏提高普通化疗剂的治疗功效的能力。因此，本研究的目的是评估芹菜素与顺铂的组合对CD 44（+）PCa干细胞生长和迁移的影响。基于铂的抗肿瘤药物已被用于治疗许多恶性肿瘤，包括PCa。然而，不幸的是，获得性耐药性和副作用限制了顺铂的使用。用人CD 44-PE抗体从人雄激素非依赖性PC 3 PCa细胞中分离出CD 44（+）亚群。MTT法测定IC 50值。采用RT-qPCR、Western blot和图像细胞仪等方法研究细胞凋亡、细胞周期及其分子机制。通过伤口愈合试验评价细胞迁移。芹菜素（15 μ M）和顺铂（7.5 μ M）的IC 50剂量的组合48小时通过下调Bcl-2、sharpin和生存素以及上调半胱天冬酶-8、Apaf-1和p53 mRNA表达显著增强顺铂的细胞毒性和凋亡作用。联合治疗抑制p-PI 3 K和p-Akt的磷酸化，抑制NF-κ B的蛋白表达，并通过上调p21以及细胞周期蛋白依赖性激酶CDK-2、-4和-6来下调细胞周期。芹菜素通过下调Snail表达显著增强顺铂对细胞迁移的抑制作用。总之，我们的研究显示了使用芹菜素通过靶向前列腺癌中的CSC亚群来潜在地增加顺铂的作用的可能的治疗方法。(C)2017 Elsevier Masson SAS。All rights reserved.
Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancerrelated death among men. Development of chemoresistance, tumor relapse and metastasis remain major barriers to effective treatment and all been identified to be associated with cancer stem cells (CSCs). Natural flavonoids such as apigenin have been shown to have the ability to improve the therapeutic efficacy of common chemotherapy agents through CSCs sensitization. Thus, the aim of this study was to evaluate the combination of apigenin with cisplatin on CD44(+) PCa stem cell growth and migration. Platinum-based anti-neoplastic drugs have been used to treat a number of malignancies including PCa. However, acquired resistance and side effects unfortunately have limited cisplatin's use. A CD44(+) subpopulation was isolated from human androgen-independent PC3 PCa cells by using human CD44-PE antibody. IC50 values were determined by MTT test. RT-qPCR, Western blot analyses and image-based cytometer were used to investigate apoptosis, cell cycle and their underlying molecular mechanisms. Cell migration was evaluated by wound healing test. The combination of the IC50 doses of apigenin (15 mu M) and cisplatin (7.5 mu M) for 48 h significantly enhanced cisplatin's cytotoxic and apoptotic effects through downregulation of Bcl-2, sharpin and survivin; and upregulation of caspase-8, Apaf-1 and p53 mRNA expression. The combined therapy suppressed the phosphorylation of p-PI3K and p-Akt, inhibited the protein expression of NF-kB, and downregulated the cell cycle by upregulating p21, as well as cyclin dependent kinases CDK-2, -4, and -6. Apigenin significantly increased the inhibitory effects of cisplatin on cell migration via downregulation of Snail expression. In conclusion, our study showed the possible therapeutic approach of using apigenin to potentially increase the effects of cisplatin by targeting CSCs subset in prostate cancer. (C) 2017 Elsevier Masson SAS. All rights reserved.