Repurposing Dihydroartemisinin to Combat Oral Squamous Cell Carcinoma, Associated with Mitochondrial Dysfunction and Oxidative Stress.
Repurposing Dihydroartemisinin to Combat Oral Squamous Cell Carcinoma, Associated with Mitochondrial Dysfunction and Oxidative Stress.
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DOI：
10.1155/2023/9595201
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发表时间：
2023
影响因子：
--
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中科院分区：
文献类型：
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口腔鳞状细胞癌（Oral squamous cell carcinoma，OSCC）是一种侵袭性强、早期复发率高、预后差的恶性肿瘤。双氢青蒿素（DHA）是青蒿素的衍生物，具有较强的抗肿瘤活性。最近的研究表明，DHA通过调节活性氧（ROS）的产生和线粒体钙单向转运体来抑制OSCC细胞的生长和活力。然而，DHA对OSCC作用的潜在机制仍然难以捉摸。在这项研究中，我们观察到159个基因在与DHA抑制途径相关的原发性OSCC肿瘤中明显失调，支持OSCC对DHA治疗敏感。在此，我们的研究表明，DHA表现出有希望的效果，抑制口腔鳞癌细胞的生长和存活，以及单细胞集落形成。有趣的是，DHA和顺铂（CDDP）的组合显著降低了单独CDDP治疗对人正常口腔细胞（NOK）的毒性。此外，DHA显著损害线粒体结构和功能，并引发DNA损伤和ROS产生，以及线粒体自噬的激活。此外，DHA诱导细胞色素C和凋亡诱导因子（AIF）从线粒体中泄漏，提高Bax/切割半胱天冬酶3的表达水平，并损害Bcl 2蛋白的表达。在OSCC肿瘤异种移植小鼠模型中，DHA显著抑制肿瘤生长并诱导OSCC体内凋亡。有趣的是，选择性线粒体自噬抑制剂Mdivi-1可以显著增强DHA治疗的抗癌活性。DHA和Mdivi-1可以协同抑制OSCC细胞增殖和存活。这些数据揭示了DHA相关途径对OSCC抗肿瘤活性的先前未被认识的贡献。我们的研究揭示了一个新的方面的DHA为基础的治疗策略，以打击口腔鳞癌肿瘤。
Oral squamous cell carcinoma (OSCC), with aggressive locoregional invasion, has a high rate of early recurrences and poor prognosis. Dihydroartemisinin (DHA), as a derivative of artemisinin, has been found to exert potent antitumor activity. Recent studies reported that DHA suppresses OSCC cell growth and viability through the regulation of reactive oxygen species (ROS) production and mitochondrial calcium uniporter. However, the mechanism underlying the action of DHA on OSCCs remains elusive. In the study, we observed that 159 genes were remarkably misregulated in primary OSCC tumors associated with DHA-inhibited pathways, supporting that OSCCs are susceptible to DHA treatment. Herein, our study showed that DHA exhibited promising effects to suppress OSCC cell growth and survival, and single-cell colony formation. Interestingly, the combination of DHA and cisplatin (CDDP) significantly reduced the toxicity of CDDP treatment alone on human normal oral cells (NOK). Moreover, DHA remarkably impaired mitochondrial structure and function, and triggered DNA damage and ROS generation, and activation of mitophagy. In addition, DHA induced leakage of cytochrome C and apoptosis-inducing factor (AIF) from mitochondria, elevated Bax/cleaved-caspase 3 expression levels and compromised Bcl2 protein expression. In the OSCC tumor-xenograft mice model, DHA remarkably suppressed tumor growth and induced apoptosis of OSCCs in vivo. Intriguingly, a selective mitophagy inhibitor Mdivi-1 could significantly reinforce the anticancer activity of DHA treatment. DHA and Mdivi-1 can synergistically suppress OSCC cell proliferation and survival. These data uncover a previously unappreciated contribution of the mitochondria-associated pathway to the antitumor activity of DHA on OSCCs. Our study shed light on a new aspect of a DHA-based therapeutic strategy to combat OSCC tumors.
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影响因子：
11.1
作者：
Bano D;Prehn JHM
通讯作者：
Prehn JHM
影响因子：
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作者：
Chaib, Imane;Cai, Xueting;Cao, Peng
通讯作者：
Cao, Peng
影响因子：
9.3
作者：
Cai, Xueting;Miao, Jing;Cao, Peng
通讯作者：
Cao, Peng
DOI：
10.4269/ajtmh.2012.12-0025
发表时间：
2012-08
期刊：
The American journal of tropical medicine and hygiene
影响因子：
--
作者：
Fairhurst RM;Nayyar GML;Breman JG;Hallett R;Vennerstrom JL;Duong S;Ringwald P;Wellems TE;Plowe CV;Dondorp AM
通讯作者：
Dondorp AM
影响因子：
--
作者：
Crespo-Ortiz MP;Wei MQ
通讯作者：
Wei MQ