姜黄素合成的纳米氧化锌通过作用于 Cox-2/NF-κB 和 p53 通路对人结肠上皮癌细胞（Caco-2）的抗肿瘤活性。
Antitumor Activity of Zinc Nanoparticles Synthesized with Berberine on Human Epithelial Colorectal Adenocarcinoma (Caco-2) Cells through Acting on Cox-2/NF-kB and p53 Pathways.
机构信息
Department of Basic Sciences, University of Ha'il, Hail, Saudi Arabia.
Faculty of Biotechnology, October University for Modern Science and Arts (MSA), Giza, Egypt.
出版信息
Anticancer Agents Med Chem. 2022;22(10):2002-2010. doi: 10.2174/1871520621666211004115839.
BACKGROUND
Drawbacks and side effects of currently available therapies to colorectal cancer (CRC) have compelled researchers to search for new therapeutic strategies.
OBJECTIVE
This study was designed to investigate the effects of zinc nanoparticles biosynthesized with berberine (ZnNPs-BER) on Caco-2 cells compared to 5-Fluorouracil (5-FU) and explore the possible underlying pathways.
METHODS
Caco-2 and Vero cells were treated with 5-FU, BER, or ZnNPs-BER for 24 h. Cell viability was measured by MTT assay. Oxidative stress and apoptotic markers and cell cycle were determined. Additionally, Cox-2 and NF-kB levels were also measured.
RESULTS
The IC50 values of 5-FU, BER, and ZnNPs-BER on Caco-2 cells were found to be 34.65 μM, 19.86 μg/ml and 10.49 μg/ml, respectively by MTT assay. The IC50 value for 5-FU in Vero cells was 21.7 μg/ml, however, BER and BER-ZnNPs treatment showed non-toxic effects on the Vero cells. Further, ZnNPs-BER exerted significant induction of ROS besides exhaustion of the antioxidant capacity of tumor cells indicated by a decline in GSH and elevated NO and MDA contents. Marked increments in levels of Bax and caspase-3 were detected together with declines in Bcl- 2 levels in Caco-2 cells subjected to BER-ZnNPs therapy. On the molecular basis, upregulation in mRNA levels of pro-apoptotic genes (Bax, caspase-3, and tumor suppressor gene p53) along with downregulation in the anti-apoptotic gene (Bcl-2) were observed in ZnNPs-BER treated Caco-2 cells. Furthermore, ZnNPs-BER showed more pronounced effects on apoptosis increased cell percentage in the S and subG1 phases. In addition, green synthesis of ZnNPs with BER showed notable induction of Cox2 and NF-kB in Caco-2 cells.
CONCLUSION
Therefore, the antitumor potential of ZnNPs-BER in colon cancer cells may be endorsed for induction of oxidative stress, inflammation, and apoptotic changes in tumor cells. Our study documents the therapeutic potential of Zn nanoparticles conjugated with BER, which may be a new option for combined chemotherapy.
背景
目前用于结直肠癌（CRC）的治疗方法存在缺陷和副作用，这促使研究人员寻找新的治疗策略。
目的
本研究旨在研究与 5-氟尿嘧啶（5-FU）相比，黄连素（BER）生物合成的锌纳米粒子（ZnNPs-BER）对 Caco-2 细胞的影响，并探讨可能的潜在途径。
方法
用 5-FU、BER 或 ZnNPs-BER 处理 Caco-2 和 Vero 细胞 24 小时。通过 MTT 测定法测量细胞活力。测定氧化应激和凋亡标志物以及细胞周期。此外，还测量了 Cox-2 和 NF-kB 水平。
结果
MTT 测定法发现，5-FU、BER 和 ZnNPs-BER 对 Caco-2 细胞的 IC50 值分别为 34.65 μM、19.86 μg/ml 和 10.49 μg/ml。5-FU 在 Vero 细胞中的 IC50 值为 21.7 μg/ml，然而，BER 和 BER-ZnNPs 处理对 Vero 细胞表现出非毒性作用。此外，ZnNPs-BER 除了耗尽肿瘤细胞的抗氧化能力（表现为 GSH 下降和 NO 和 MDA 含量升高）外，还显著诱导了 ROS 的产生。BER-ZnNPs 治疗的 Caco-2 细胞中 Bax 和 caspase-3 水平显著升高，同时 Bcl-2 水平下降。在分子基础上，在 ZnNPs-BER 处理的 Caco-2 细胞中，促凋亡基因（Bax、caspase-3 和肿瘤抑制基因 p53）的 mRNA 水平上调，而抗凋亡基因（Bcl-2）下调。此外，ZnNPs-BER 对细胞周期中 S 期和亚 G1 期的细胞百分比的凋亡增加有更显著的作用。此外，BER 与 ZnNPs 的绿色合成在 Caco-2 细胞中显着诱导了 Cox2 和 NF-kB。
结论
因此，ZnNPs-BER 在结肠癌细胞中的抗肿瘤潜力可能归因于诱导肿瘤细胞发生氧化应激、炎症和凋亡变化。我们的研究证明了与 BER 结合的 Zn 纳米粒子的治疗潜力，这可能是联合化疗的新选择。
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