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5-氟尿嘧啶联合负载抗氧化剂百里醌的碳酸钙纳米颗粒抗结肠癌：协同治疗潜力及潜在分子机制

5-Fluorouracil in Combination with Calcium Carbonate Nanoparticles Loaded with Antioxidant Thymoquinone against Colon Cancer: Synergistically Therapeutic Potential and Underlying Molecular Mechanism.

作者信息

Deng Xi, Yang Zhongming, Chan Kim Wei, Ismail Norsharina, Abu Bakar Md Zuki

机构信息

Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.

Department of Veterinary Preclinical Science, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.

出版信息

Antioxidants (Basel). 2024 Aug 25;13(9):1030. doi: 10.3390/antiox13091030.

DOI:10.3390/antiox13091030
PMID:39334689
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11429434/
Abstract

Colon cancer is the third most common cancer worldwide, with high mortality. Adverse side effects and chemoresistance of the first-line chemotherapy 5-fluorouracil (5-FU) have promoted the widespread use of combination therapies. Thymoquinone (TQ) is a natural compound with potent antioxidant activity. Loading antioxidants into nano delivery systems has been a major advance in enhancing their bioavailability to improve clinical application. Hence, this study aimed to prepare the optimal TQ-loaded calcium carbonate nanoparticles (TQ-CaCO NPs) and investigate their therapeutic potential and underlying molecular mechanisms of TQ-CaCO NPs in combination with 5-FU against colon cancer. Firstly, we developed purely aragonite CaCO NPs with a facile mechanical ball-milling method. The pH-sensitive and biocompatible TQ-CaCO NPs with sustained release properties were prepared using the optimal synthesized method (a high-speed homogenizer). The in vitro study revealed that the combination of TQ-CaCO NPs (15 μM) and 5-FU (7.5 μM) inhibited CT26 cell proliferation and migration, induced cell apoptosis and cell cycle arrest in the G/G phase, and suppressed the CT26 spheroid growth, exhibiting a synergistic effect. Finally, network pharmacology and molecular docking results indicated the potential targets and crucial signaling pathways of TQ-CaCO NPs in combination with 5-FU against colon cancer. Therefore, TQ-CaCO NPs combined with 5-FU could enhance the anti-colon cancer effects of 5-FU with broader therapeutic targets, warranting further application for colon cancer treatment.

摘要

结肠癌是全球第三大常见癌症，死亡率很高。一线化疗药物5-氟尿嘧啶（5-FU）的不良副作用和化疗耐药性促使联合疗法得到广泛应用。胸腺醌（TQ）是一种具有强大抗氧化活性的天然化合物。将抗氧化剂载入纳米递送系统是提高其生物利用度以改善临床应用的一项重大进展。因此，本研究旨在制备最佳的载胸腺醌碳酸钙纳米颗粒（TQ-CaCO NPs），并研究其与5-FU联合抗结肠癌的治疗潜力及潜在分子机制。首先，我们采用简便的机械球磨法制备了纯文石型CaCO NPs。使用最佳合成方法（高速匀浆器）制备了具有pH敏感性、生物相容性和缓释特性的TQ-CaCO NPs。体外研究表明，TQ-CaCO NPs（15 μM）与5-FU（7.5 μM）联合使用可抑制CT26细胞增殖和迁移，诱导细胞凋亡并使细胞周期停滞在G/G期，还能抑制CT26球体生长，呈现出协同效应。最后，网络药理学和分子对接结果表明了TQ-CaCO NPs与5-FU联合抗结肠癌的潜在靶点和关键信号通路。因此，TQ-CaCO NPs与5-FU联合使用可增强5-FU的抗结肠癌效果，具有更广泛的治疗靶点，值得进一步应用于结肠癌治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/e607bb94af07/antioxidants-13-01030-g010a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/31fba3f0254a/antioxidants-13-01030-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/cbe0d9f1d158/antioxidants-13-01030-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/16ee62731e54/antioxidants-13-01030-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/ecf0b2521d6a/antioxidants-13-01030-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/5e7e8680b4da/antioxidants-13-01030-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/50de719e0ee3/antioxidants-13-01030-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/430c2149dd98/antioxidants-13-01030-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/e768f2648f29/antioxidants-13-01030-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/3a6118eec6c0/antioxidants-13-01030-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/e607bb94af07/antioxidants-13-01030-g010a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/31fba3f0254a/antioxidants-13-01030-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/cbe0d9f1d158/antioxidants-13-01030-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/16ee62731e54/antioxidants-13-01030-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/ecf0b2521d6a/antioxidants-13-01030-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/5e7e8680b4da/antioxidants-13-01030-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/50de719e0ee3/antioxidants-13-01030-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/430c2149dd98/antioxidants-13-01030-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/e768f2648f29/antioxidants-13-01030-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/3a6118eec6c0/antioxidants-13-01030-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a298/11429434/e607bb94af07/antioxidants-13-01030-g010a.jpg

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[2]
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[3]
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Int J Mol Sci. 2024-12-3

本文引用的文献

[1]
Exploring the Therapeutic Potential of 5-Fluorouracil-Loaded Calcium Carbonate Nanoparticles Combined with Natural Compound Thymoquinone for Colon Cancer Treatment.

Pharmaceutics. 2024-7-30

[2]
Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.

CA Cancer J Clin. 2024

[3]
High Oestrogen receptor alpha expression correlates with adverse prognosis and promotes metastasis in colorectal cancer.

Cell Commun Signal. 2024-3-28

[4]
Pathological and pharmacological functions of the metabolites of polyunsaturated fatty acids mediated by cyclooxygenases, lipoxygenases, and cytochrome P450s in cancers.

Pharmacol Ther. 2024-4

[5]
Measurement and Correlation of the Solubility of 5-Fluorouracil in Pure and Binary Solvents.

J Chem Eng Data. 2018-10-11

[6]
Assessing toxicity mechanism of silver nanoparticles by using brine shrimp (Artemia salina) as model.

Chemosphere. 2024-1

[7]
Layer-by-layer coated calcium carbonate nanoparticles for targeting breast cancer cells.

Biomater Adv. 2023-10

[8]
Thymoquinone protects against 5-Fluorouracil-induced mucositis by NF-κβ and HIF-1 mechanisms in mice.

J Biochem Mol Toxicol. 2023-9

[9]
Calcium carbonate nanoparticles tumor delivery for combined chemo-photodynamic therapy: Comparison of local and systemic administration.

J Control Release. 2023-7

[10]
The processes behind drug loading and release in porous drug delivery systems.

Eur J Pharm Biopharm. 2023-8

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