Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India.
Environ Toxicol. 2022 Feb;37(2):256-269. doi: 10.1002/tox.23395. Epub 2021 Nov 2.
The oceans are considered as magnificent source of bioactive metabolites, of which marine sponges associated organisms are being the most effective producers of various bioactive molecules. We previously reported that cyclo(-Pro-Tyr) (CPT), a dipeptide from marine sponge Callyspongia fistularis associated Bacillus pumilus AMK1 bacteria for its anti-proliferative activity through down regulating PI3K signaling and inducing mitochondrial mediated apoptosis in HepG2 cells. Further we emphasize to study the role of CPT against hepatocellular carcinoma (HCC) induced by N-diethylnitrosamine (DEN) in male swiss albino mice in vivo. In this study, HCC was induced by the administration of DEN (75 mg/kg b.wt) dissolved in saline once/week for 3 weeks, then 100 mg/kg b.wt for another successive 3 weeks and observed for 18 weeks. CPT (100 mg/kg b.wt) treatment was started after 14 weeks of DEN induction. The obtained results demonstrated that CPT altered DEN induced oxidative stress by decreasing serum SGOT and SGPT followed increment in the antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. This was accompanied by decreased accumulation of glycoconjugates and argyophilic nucleolar organizing regions in the treatment groups. Further, CPT significantly reduced the levels of phospho-PI3Kinase p85 and phospho-AKT and upregulation of PTEN compared with DEN induced group. Besides this, decreased expression of Bcl-2 and increased expression of Bax, Caspase 3, and p53 was observed in CPT treated mice. Therefore, the anticancer mechanism of CPT against DEN induced HCC may be associated with the regulation of the PI3K/AKT signaling pathway, which ultimately stimulates apoptosis.
海洋被认为是生物活性代谢物的壮丽来源，其中与海洋海绵相关的生物体是各种生物活性分子的最有效生产者。我们之前报道过，环(-脯氨酸-酪氨酸)(CPT)，一种来自海洋海绵 Callyspongia fistularis 的二肽，与 Bacillus pumilus AMK1 细菌有关，通过下调 PI3K 信号通路和诱导 HepG2 细胞中线粒体介导的细胞凋亡来发挥其抗增殖活性。此外，我们强调研究 CPT 对体内雄性瑞士白化小鼠 N-二乙基亚硝胺(DEN)诱导的肝细胞癌(HCC)的作用。在这项研究中，DEN(75mg/kg b.wt)溶于生理盐水，每周一次，连续 3 周给药，诱导 HCC，然后连续 3 周给予 100mg/kg b.wt，观察 18 周。CPT(100mg/kg b.wt)治疗在 DEN 诱导 14 周后开始。结果表明，CPT 通过降低血清 SGOT 和 SGPT，增加抗氧化剂如超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶和谷胱甘肽还原酶，改变 DEN 诱导的氧化应激。这伴随着治疗组中糖缀合物和嗜银核仁组成区的积累减少。此外，与 DEN 诱导组相比，CPT 显著降低了磷酸化 PI3K p85 和磷酸化 AKT 的水平，并上调了 PTEN。除此之外，在 CPT 处理的小鼠中观察到 Bcl-2 表达降低和 Bax、Caspase 3 和 p53 表达增加。因此，CPT 对 DEN 诱导的 HCC 的抗癌机制可能与调节 PI3K/AKT 信号通路有关，这最终刺激细胞凋亡。
