Gomathinayagam Sankaranarayanan, Srinivasan Ramachandran, Gomathi Ajitha, Jayaraj Rama, Vasconcelos Vitor, Sudhakaran Raja, Easwaran Nalini, Kodiveri Muthukaliannan Gothandam
School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
Centre for Ocean Research (DST-FIST Sponsored Centre), MoES - Earth Science & Technology Cell, Sathyabama Research Park, Sathyabama Institute of Science and Technology, Chennai, 600119, Tamil Nadu, India.
Appl Biochem Biotechnol. 2025 Jan;197(1):159-178. doi: 10.1007/s12010-024-05024-z. Epub 2024 Aug 6.
The present study aims to investigate the oral therapeutic and molecular role of carotenoid-rich Dunaliella salina powder (DSP) against 1,2-dimethylhydrazine (DMH)-triggered colon carcinogenesis. In this study, thirty six male Wistar rats were categorized into six distinct groups (G1-G6): G1 group with no intervention, G2 group received only DSP (1000 mg/kg), G3 group received only DMH carcinogen (20 mg/kg), and G4-G6 group received both DMH and DSP at various phases (pre-initiation, post-initiation and entire phases) for 32 weeks. Body weight, tumor incidence, tumor volume, histopathological examination, antioxidants, and detoxification enzymes activities were analyzed in the experimental rats. In addition, the protein expression profile of components involved in the Wnt/β-catenin signaling pathway was determined by western blot analysis. Matrix metalloproteinases (MMP-7 and MMP-9), proliferation marker (PCNA), and pro-apoptotic (Bcl-2 and Bax) proteins were analyzed using immunohistochemistry. Colorimetric assay was used to determine the levels of anti-inflammatory (iNOS and COX-2) and apoptotic proteins (Caspase-3 and Caspase-9). Results showed that concomitant administration of DSP with DMH significantly reduced tumor progression and prevented colon carcinogenesis in rats. However, treatment with DSP before or after DMH exposure did not significantly prevent colon carcinogenesis. DMH and DSP treatment group showed increased activities of antioxidant enzymes with significant reduction in the oxidative stress. Additionally, the detoxification enzymes and colonic histopathology of those rats were restored to that of control rats. The administration of DSP to rats exposed to DMH exhibited antitumor effects via inhibition of the Wnt/β-catenin signaling pathway with induced apoptosis through the Bcl-2/Bax/caspases signaling cascades. Moreover, the same group also showed significant anti-inflammatory activity via regulating iNOS and COX-2 biomarkers. Our findings revealed molecular chemopreventive activity of carotenoid-rich DSP through regulating Wnt/beta-catenin and intrinsic apoptotic pathways. Thus, DSP is propound to function as a potent antioxidant, anti-proliferative, and anti-inflammatory therapeutic agent against colon carcinogenesis.
本研究旨在探讨富含类胡萝卜素的盐生杜氏藻粉（DSP）对1,2 - 二甲基肼（DMH）诱发的结肠癌发生的口服治疗作用及分子机制。在本研究中，36只雄性Wistar大鼠被分为六个不同的组（G1 - G6）：G1组无干预，G2组仅接受DSP（1000毫克/千克），G3组仅接受DMH致癌物（20毫克/千克），G4 - G6组在不同阶段（起始前、起始后和整个阶段）同时接受DMH和DSP，持续32周。对实验大鼠的体重、肿瘤发生率、肿瘤体积、组织病理学检查、抗氧化剂以及解毒酶活性进行了分析。此外，通过蛋白质免疫印迹分析确定了Wnt/β - 连环蛋白信号通路相关成分的蛋白质表达谱。使用免疫组织化学分析基质金属蛋白酶（MMP - 7和MMP - 9）、增殖标志物（PCNA）以及促凋亡（Bcl - 2和Bax）蛋白。采用比色法测定抗炎（iNOS和COX - 2）和凋亡蛋白（Caspase - 3和Caspase - 9）的水平。结果表明，DSP与DMH联合给药显著降低了肿瘤进展并预防了大鼠结肠癌的发生。然而，在DMH暴露之前或之后用DSP治疗并不能显著预防结肠癌的发生。DMH和DSP治疗组的抗氧化酶活性增加，氧化应激显著降低。此外，这些大鼠的解毒酶和结肠组织病理学恢复到了对照大鼠的水平。给暴露于DMH的大鼠施用DSP通过抑制Wnt/β - 连环蛋白信号通路并通过Bcl - 2/Bax/半胱天冬酶信号级联诱导凋亡而表现出抗肿瘤作用。此外，同一组还通过调节iNOS和COX - 2生物标志物表现出显著的抗炎活性。我们的研究结果揭示了富含类胡萝卜素的DSP通过调节Wnt/β - 连环蛋白和内在凋亡途径的分子化学预防活性。因此，DSP被认为是一种有效的抗氧化、抗增殖和抗炎治疗剂，可对抗结肠癌的发生。
