Seydi Enayatollah, Motallebi Abbasali, Dastbaz Maryam, Dehghan Sahar, Salimi Ahmad, Nazemi Melika, Pourahmad Jalal
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran.
Research and Education and Extension Organization (AREEO) and Iranian Fisheries Research Organization, Ministry of Jihad-e-Agriculture, Tehran, IR Iran.
Hepat Mon. 2015 Dec 27;15(12):e33073. doi: 10.5812/hepatmon.33073. eCollection 2015 Dec.
Natural products isolated from marine environments are well known for their pharmacodynamic potential in diverse disease treatments, such as for cancer or inflammatory conditions. Sea cucumbers are marine animals of the phylum Echinoderm and the class Holothuroidea, with leathery skin and gelatinous bodies. Sponges are important components of Persian Gulf animal communities, and the marine sponges of the genus Haliclona have been known to display broad-spectrum biological activity. Many studies have shown that sea cucumbers and sponges contain antioxidants and anti-cancer compounds.
This study was designed to determine the selective toxicity of Persian Gulf sea cucumber (Holothuria parva) and sponge (Haliclona oculata) methanolic extracts on liver mitochondria isolated from an animal model of hepatocellular carcinoma, as part of a national project that hopes to identify novel potential anticancer candidates among Iranian Persian Gulf flora and fauna.
To induce hepatocarcinogenesis, rats were given diethylnitrosamine (DEN) injections (200 mg/kg i.p. by a single dose), and then the cancer was promoted with 2-acetylaminofluorene (2-AAF) (0.02 w/w) for two weeks. Histopathological evaluations were performed, and levels of liver injury markers and a specific liver cancer marker (alpha-fetoprotein), were determined for confirmation of hepatocellular carcinoma induction. Finally, mitochondria were isolated from cancerous and non-cancerous hepatocytes.
Our results showed that H. parva methanolic extracts (250, 500, and 1000 µg/mL) and H. oculata methanolic extracts (200, 400, and 800 µg/mL) increased reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP), mitochondrial swelling, and cytochrome c release in the mitochondria obtained from cancerous hepatocytes, but not in mitochondria obtained from non-cancerous liver hepatocytes. These extracts also induced caspase-3 activation, which is known as a final mediator of apoptosis, in the hepatocytes obtained only from cancerous, not non-cancerous, rat livers.
Our results suggest that H. parva and H. oculata may be promising therapeutic candidates for the treatment of HCC, following further confirmatory in vivo experiments and clinical trials.
从海洋环境中分离出的天然产物因其在多种疾病治疗中的药效潜力而闻名，如癌症或炎症性疾病的治疗。海参是棘皮动物门海参纲的海洋动物，具有革质皮肤和凝胶状身体。海绵是波斯湾动物群落的重要组成部分，已知Haliclona属的海洋海绵具有广谱生物活性。许多研究表明，海参和海绵含有抗氧化剂和抗癌化合物。
本研究旨在确定波斯湾海参（小海参）和海绵（眼状Haliclona海绵）甲醇提取物对从肝细胞癌动物模型中分离出的肝线粒体的选择性毒性，这是一个国家项目的一部分，该项目希望在伊朗波斯湾动植物中鉴定出新的潜在抗癌候选物。
为诱导肝癌发生，给大鼠腹腔注射二乙基亚硝胺（DEN）（单次剂量200mg/kg），然后用2-乙酰氨基芴（2-AAF）（0.02w/w）促进癌症发展两周。进行组织病理学评估，并测定肝损伤标志物和特定肝癌标志物（甲胎蛋白）的水平，以确认肝细胞癌的诱导情况。最后，从癌性和非癌性肝细胞中分离出线粒体。
我们的结果表明，小海参甲醇提取物（250、500和1000μg/mL）和眼状Haliclona海绵甲醇提取物（200、400和800μg/mL）增加了从癌性肝细胞获得的线粒体中的活性氧（ROS）形成、线粒体膜电位（MMP）、线粒体肿胀和细胞色素c释放，但在从非癌性肝肝细胞获得的线粒体中未出现这种情况。这些提取物还仅在从癌性大鼠肝脏而非非癌性大鼠肝脏获得的肝细胞中诱导了半胱天冬酶-3激活，半胱天冬酶-3激活是已知的细胞凋亡最终介质。
我们的结果表明，在进一步的体内实验和临床试验得到证实后，小海参和眼状Haliclona海绵可能是治疗肝癌的有前景的治疗候选物。
