Faculty of Marine Sciences, Center for Advanced Sciences, Annamalai University, Parangipettai, TN, India.
Stephenson Cancer Center, Oklahoma City, OK, USA.
Mol Cell Biochem. 2019 Oct;460(1-2):175-193. doi: 10.1007/s11010-019-03579-8. Epub 2019 Jul 31.
The upsurge of marine-derived therapeutics for cancer treatment is evident, with many drugs in clinical use and in clinical trials. Seaweeds harbor large amounts of polyphenols and their anti-cancer benefit is linear to their anti-oxidant activity. Our studies identified three superlative anti-cancer seaweed polyphenol drug candidates (SW-PD). We investigated the acquisition of oncogenic burden in radiation-resilient pancreatic cancer (PC) that could drive tumor relapse, and elucidated the efficacy of SW-PD candidates as adjuvants in genetically diverse in vitro systems and a mouse model of radiation-residual disease. QPCR profiling of 88 oncogenes in therapy-resilient PC cells identified a 'shared' activation of 40 oncogenes. SW-PD pretreatment inflicted a significant mitigation of acquired (shared) oncogenic burden, in addition to drug- and cell-line-specific repression signatures. Tissue microarray with IHC of radiation-residual tumors in mice signified acquired cellular localization of key oncoproteins and other critical architects. Conversely, SW-PD treatment inhibited the acquisition of these critical drivers of tumor genesis, dissemination, and evolution. Heightened death of resilient PC cells with SW-PD treatment validated the translation aspects. The results defined the acquisition of oncogenic burden in resilient PC and demonstrated that the marine polyphenols effectively target the acquired oncogenic burden and could serve as adjuvant(s) for PC treatment.
海洋来源的癌症治疗药物的热潮显而易见，许多药物已在临床使用和临床试验中。海藻中含有大量的多酚，其抗癌作用与其抗氧化活性呈线性关系。我们的研究确定了三种卓越的抗癌海藻多酚药物候选物（SW-PD）。我们研究了辐射抗性胰腺癌（PC）中致癌负担的获得，这些负担可能导致肿瘤复发，并阐明了 SW-PD 候选物作为基因多样化体外系统和辐射残留疾病小鼠模型的辅助药物的功效。对治疗耐药性 PC 细胞中的 88 种致癌基因进行 QPCR 分析，确定了 40 种致癌基因的“共享”激活。SW-PD 预处理除了具有药物和细胞系特异性的抑制特征外，还能显著减轻获得的（共享）致癌负担。对小鼠辐射残留肿瘤的组织微阵列和免疫组化分析表明，关键致癌蛋白和其他关键架构蛋白的细胞定位获得。相反，SW-PD 治疗抑制了这些肿瘤发生、扩散和进化的关键驱动因素的获得。SW-PD 治疗使耐药性 PC 细胞死亡增加，验证了其转化方面的意义。结果定义了耐药性 PC 中致癌负担的获得，并表明海洋多酚可有效靶向获得的致癌负担，并可作为 PC 治疗的辅助药物。
