Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, 22030, Edirne, Turkey.
Department of Biochemistry, School of Medicine, Trakya University, Balkan Campus, 22030 Edirne, Turkey.
Invest New Drugs. 2020 Apr;38(2):246-263. doi: 10.1007/s10637-019-00774-8. Epub 2019 Apr 16.
Prostate cancer (PCa) is the most common cancer in men worldwide. Midkine (MK) is overexpressed in PCa, as well as in tumor-initiating cells termed cancer stem cells (CSCs). Apigenin is a dietary flavone with considerable anti-tumor activities. In this study, we explored the possible therapeutic use of MK silencing, apigenin treatment, and a combination of both on human PCa and prostate cancer stem cells (PCSCs). CD44CD133 PC3 and CD44 LNCaP CSCs were isolated from their parent cell lines. Both MK knockdown and apigenin treatment resulted in loss of cell viability in PCSCs, and these effects were significantly elevated when apigenin was applied with MK silencing. Combined treatment of CD44CD133 PC3 cells with apigenin and MK siRNA was also more effective in inducing apoptotic and non-apoptotic cell death when compared with individual applications. Treatment of CD44 LNCaP cells with apigenin significantly decreased viability, although the combination treatment did not markedly alter the individual therapy. Molecular events underlying cell cycle arrest and inhibition of the survival, proliferation, and migration of CD44CD133 PC3 cells were found to be associated with upregulated p21, p27, Bax, Bid, caspase-3, and caspase-8 expression, as well as downregulated p-p38, p-ERK, NF-κB, and PARP. In addition, the combination of apigenin treatment and MK silencing showed better outcomes on the anticancer efficacy of docetaxel in CD44CD133 PC3 cells. In conclusion, MK-regulated events are different between PCSCs, and when combined with apigenin plus MK silencing, docetaxel treatment may be a valuable approach for the eradication of PCSCs.
前列腺癌（PCa）是全球男性最常见的癌症。中期因子（MK）在 PCa 以及被称为癌症干细胞（CSCs）的肿瘤起始细胞中过度表达。芹菜素是一种具有相当抗肿瘤活性的膳食类黄酮。在这项研究中，我们探讨了 MK 沉默、芹菜素处理以及两者联合应用于人类前列腺癌和前列腺癌干细胞（PCSCs）的可能治疗用途。CD44CD133 PC3 和 CD44 LNCaP CSCs 从其亲本细胞系中分离出来。MK 敲低和芹菜素处理都导致 PCSCs 的细胞活力丧失，当用 MK 沉默联合应用芹菜素时，这些效果显著提高。与单独应用相比，联合处理 CD44CD133 PC3 细胞的芹菜素和 MK siRNA 也更有效地诱导凋亡和非凋亡细胞死亡。尽管联合治疗并未显著改变单独治疗的效果，但芹菜素处理 CD44 LNCaP 细胞可显著降低细胞活力。细胞周期停滞和抑制 CD44CD133 PC3 细胞存活、增殖和迁移的分子事件与上调的 p21、p27、Bax、Bid、caspase-3 和 caspase-8 表达以及下调的 p-p38、p-ERK、NF-κB 和 PARP 表达相关。此外，与单独应用相比，在 CD44CD133 PC3 细胞中，联合应用芹菜素处理和 MK 沉默可提高多西他赛的抗癌疗效。总之，PCSCs 中的 MK 调节事件不同，当与芹菜素联合应用时，多西他赛治疗可能是根除 PCSCs 的一种有价值的方法。
