Robinson Glenn F, Sooda Kartheek Ky, Phillips Roger M, Allison Simon J, Javid Farideh A
Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, UK.
Curr Res Pharmacol Drug Discov. 2022 Jan 19;3:100085. doi: 10.1016/j.crphar.2022.100085. eCollection 2022.
The aim of the present study was to investigate the cytotoxicity induced by an omega-3 derivative, didocosahexaenoin (Dido) on human prostate carcinoma cells and to compare the cytotoxicity to that of docosahexaenoic acid (DHA). Different carcinoma- and non-carcinoma cells were exposed to various concentrations of omega-3 compounds at varying exposure times and the cytotoxicity was measured by MTT assay. The mechanism of Dido-induced apoptosis was investigated in prostate carcinoma cells. Dido induced stronger cytotoxicity than DHA in human prostate carcinoma cells in a dose- and time-dependent manner. Dido was also more selective and potent in inducing cytotoxicity in prostate carcinoma cells than other carcinoma cell lines tested. Pre-treatment with Dido increased the level of reactive oxygen species (ROS) in prostate carcinoma cells. Pre-treatment with various antioxidants reduced the cytotoxicity induced by Dido. Pre-treatment with Dido ≥30 μM also induced apoptosis which was suggested to involve an externalisation of phosphatidyl serine, a significant increase in the mitochondrial membrane potential (p < 0.01) and the level of activated caspase 3/7 (p < 0.05) in prostate carcinoma cells. This study is the first to show that Dido induced cytotoxicity with high selectivity and higher potency than DHA in human prostate carcinoma cells. The mechanism of action is likely to involve an increase in the level of ROS, loss in the mitochondrial membrane potential as well as externalisation of phosphatidyl serine and increase in the caspase 3/7 activity. Dido may have potential to be used for the adjuvant therapy or combination therapy with conventional chemotherapeutic drugs.
本研究的目的是调查ω-3衍生物二十二碳六烯酸二甘油酯（Dido）对人前列腺癌细胞的细胞毒性，并将其细胞毒性与二十二碳六烯酸（DHA）的细胞毒性进行比较。将不同的癌细胞和非癌细胞在不同的暴露时间下暴露于不同浓度的ω-3化合物中，并通过MTT法测量细胞毒性。在前列腺癌细胞中研究了Dido诱导凋亡的机制。Dido在人前列腺癌细胞中以剂量和时间依赖性方式诱导比DHA更强的细胞毒性。与其他测试的癌细胞系相比，Dido在诱导前列腺癌细胞的细胞毒性方面也更具选择性和效力。用Dido预处理可增加前列腺癌细胞中活性氧（ROS）的水平。用各种抗氧化剂预处理可降低Dido诱导的细胞毒性。用≥30μM的Dido预处理也可诱导凋亡，这表明其涉及前列腺癌细胞中磷脂酰丝氨酸的外化、线粒体膜电位的显著增加（p<0.01）以及活化的半胱天冬酶3/7水平的增加（p<0.05）。本研究首次表明，Dido在人前列腺癌细胞中诱导的细胞毒性具有高选择性且效力高于DHA。其作用机制可能涉及ROS水平的增加、线粒体膜电位的丧失以及磷脂酰丝氨酸的外化和半胱天冬酶3/7活性的增加。Dido可能有潜力用于辅助治疗或与传统化疗药物联合治疗。
