Zhan Wei, Liao Xin, Li Lianghe, Chen Zhongsheng, Tian Tian, Yu Lei, Chen Zupeng
Department of Colorectal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, People's Republic of China.
Department of Imaging, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, People's Republic of China.
Onco Targets Ther. 2019 Sep 6;12:7297-7306. doi: 10.2147/OTT.S207640. eCollection 2019.
Reactive oxygen species (ROS) are major contributors to cancer and involved in numerous tumor proliferation signaling pathways. Mitochondria are the major ROS-producing organelles, and ROS are produced from the synthesis of adenosine triphosphate and cell metabolism.
A novel mitochondria-targeted peptide, namely KRSH, was synthesized and characterized. KRSH consists of four amino acids; lysine and arginine contain positively charged groups that help KRSH target the mitochondria, while tyrosine and cysteine neutralize excessive endogenous ROS, thereby inhibiting tumorigenesis.
The results indicated that KRSH is specifically inhibiting the growth of HeLa and MCF-7 cancer cell lines. However, MCF10A cells can resist the effects of KRSH even in a relative higher concentration. The dichloro-dihydro-fluorescein diacetate and MitoSOX Red assay suggested that KRSH drastically decreased the level of ROS in cancer cells. The mitochondrial depolarization assay indicated that treatment with KRSH at a dose of 50 nM may decrease the mitochondrial membrane potential leading to apoptosis of HeLa and MCF-7 cells.
In other studies, investigating rat liver mitochondria, the uptake of KRSH may reach 80% compared with that for mitoquinone. Therefore, KRSH was designed as a superior peptide antioxidant and a mitochondria-targeting anticancer agent.
活性氧（ROS）是癌症的主要促成因素，并参与众多肿瘤增殖信号通路。线粒体是产生ROS的主要细胞器，ROS由三磷酸腺苷的合成和细胞代谢产生。
合成并表征了一种新型的线粒体靶向肽，即KRSH。KRSH由四个氨基酸组成；赖氨酸和精氨酸含有带正电荷的基团，有助于KRSH靶向线粒体，而酪氨酸和半胱氨酸可中和过量的内源性ROS，从而抑制肿瘤发生。
结果表明，KRSH能特异性抑制HeLa和MCF-7癌细胞系的生长。然而，MCF10A细胞即使在相对较高浓度下也能抵抗KRSH的作用。二氯二氢荧光素二乙酸酯和MitoSOX Red检测表明，KRSH能显著降低癌细胞中的ROS水平。线粒体去极化检测表明，50 nM剂量的KRSH处理可能会降低线粒体膜电位，导致HeLa和MCF-7细胞凋亡。
在其他研究中，对大鼠肝线粒体的研究表明，与米托醌相比，KRSH的摄取率可能达到80%。因此，KRSH被设计为一种优质的肽抗氧化剂和线粒体靶向抗癌剂。
