Schuster Caroline, Wolpert Nicholas, Moustaid-Moussa Naima, Gollahon Lauren S
Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
Nutritional Sciences Department, Texas Tech University, Lubbock, TX 79409, USA.
Antioxidants (Basel). 2022 Mar 20;11(3):591. doi: 10.3390/antiox11030591.
Major obstacles in current breast cancer treatment efficacy include the ability of breast cancer cells to develop resistance to chemotherapeutic drugs and the off-target cytotoxicity of these drugs on normal cells, leading to debilitating side effects. One major difference between cancer and normal cells is their metabolism, as cancer cells acquire glycolytic and mitochondrial metabolism alterations throughout tumorigenesis. In this study, we sought to exploit this metabolic difference by investigating alternative breast cancer treatment options based on the application of phytochemicals. Herein, we investigated three phytochemicals, namely cinnamaldehyde (CA), chlorogenic acid (CGA), and arctigenin (Arc), regarding their anti-breast-cancer properties. These phytochemicals were administered alone or in combination to MCF-7, MDA-MB-231, and HCC1419 breast cancer or normal MCF-10A and MCF-12F breast cells. Overall, our results indicated that the combination treatments showed stronger inhibitory effects on breast cancer cells versus single treatments. However, only treatments with CA (35 μM), CGA (250 μg/mL), and the combination of CA + CGA (35 μM + 250 μg/mL) showed no significant cytotoxic effects on normal mammary epithelial cells, suggesting that Arc was the driver of normal cell cytotoxicity in all other treatments. CA + CGA and, to a lesser extent, CGA alone effectively induced breast cancer cell death accompanied by decreases in mitochondrial membrane potential, increased mitochondrial superoxide, reduced mitochondrial and glycolytic ATP production, and led to significant changes in cellular and mitochondrial morphology. Altogether, the combination of CA + CGA was determined as the best anti-breast-cancer treatment strategy due to its strong anti-breast-cancer effects without strong adverse effects on normal mammary epithelial cells. This study provides evidence that targeting the mitochondria may be an effective anticancer treatment, and that using phytochemicals or combinations thereof offers new approaches in treating breast cancer that significantly reduce off-target effects on normal cells.
当前乳腺癌治疗效果的主要障碍包括乳腺癌细胞对化疗药物产生耐药性的能力以及这些药物对正常细胞的脱靶细胞毒性，从而导致使人虚弱的副作用。癌细胞与正常细胞的一个主要区别在于它们的代谢，因为癌细胞在整个肿瘤发生过程中会发生糖酵解和线粒体代谢改变。在本研究中，我们试图通过研究基于植物化学物质应用的替代乳腺癌治疗方案来利用这种代谢差异。在此，我们研究了三种植物化学物质，即肉桂醛（CA）、绿原酸（CGA）和牛蒡子苷元（Arc）的抗乳腺癌特性。这些植物化学物质单独或联合应用于MCF-7、MDA-MB-231和HCC1419乳腺癌细胞或正常的MCF-10A和MCF-12F乳腺细胞。总体而言，我们的结果表明，联合治疗对乳腺癌细胞的抑制作用比单一治疗更强。然而，只有CA（35 μM）、CGA（250 μg/mL）以及CA + CGA（35 μM + 250 μg/mL）的联合治疗对正常乳腺上皮细胞没有显著的细胞毒性作用，这表明在所有其他治疗中Arc是正常细胞细胞毒性的驱动因素。CA + CGA以及单独使用CGA（程度较轻）能有效诱导乳腺癌细胞死亡，同时伴随着线粒体膜电位降低、线粒体超氧化物增加、线粒体和糖酵解ATP生成减少，并导致细胞和线粒体形态发生显著变化。总之，CA + CGA的联合治疗因其对乳腺癌有强大的抗癌作用且对正常乳腺上皮细胞没有强烈的不良反应，被确定为最佳的抗乳腺癌治疗策略。本研究提供了证据表明靶向线粒体可能是一种有效的抗癌治疗方法，并且使用植物化学物质或其组合为治疗乳腺癌提供了新的方法，可显著减少对正常细胞的脱靶效应。
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