Deka S J, Gorai S, Manna D, Trivedi V
Malaria Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology- Guwahati, Guwahati-781039, Assam. India.
Department of Chemistry, Indian Institute of Technology- Guwahati, Guwahati-781039, Assam. India.
Curr Mol Med. 2017;17(1):79-89. doi: 10.2174/1566524017666170209160619.
Chlorogenic acid (CGA) exhibits potentials towards liver, breast and skin cancer. Cancer cells stimulated with CGA exhibits differential expression of transcriptional factors and regulatory molecules but the molecular target of the molecule is not known. Superposition of biophoric elements of CGA with Curcumin gives maximum common substructure score of 0.90. Molecular modeling studies further suggest that CGA fits into the C1b domain of PKC with extensive interaction with residues lining binding site. It binds PKC in a concentration dependent manner with dissociation constant KD, 28.84±3.95 μM. PKC-CGA complex is stable with minimal distortion to the 3-D structure and maintains the hydrogen bonding between ligand and receptor during simulation period. Cells stimulated with CGA causes 12.1 ± 0.56% PKC translocation from the cytosol to the plasma membrane. It disturbs the cell cycle and arrest the cancer cell at the G1 phase with a reduction in S-phase. Chlorogenic acid exhibits killing of cancer cells in a dose-dependent manner with an IC50 of 75.88 ± 4.54μg/ml and 52.5 ± 4.72μg/ml towards MDAMB-231 and MCF-7 cells respectively. It induces apoptosis in cancer cells as evident by AO/EtBr staining and degradation of genomic DNA to give a laddering pattern. Apoptosis in cancer cells involves mitochondrial pathway as supported by a reduction in mitochondrial potentials and release of cyt-C into the cytosol. Hence, the current study has established PKC as an important signaling molecule to the observed anti-cancer effects of CGA and provides the impetus to design better CGA analogs for improved anti-cancer potential against the malignant tumor.
绿原酸（CGA）对肝癌、乳腺癌和皮肤癌具有潜在作用。用CGA刺激的癌细胞表现出转录因子和调节分子的差异表达，但该分子的分子靶点尚不清楚。CGA的生物活性元素与姜黄素的叠加给出的最大公共子结构得分是0.90。分子建模研究进一步表明，CGA可与蛋白激酶C（PKC）的C1b结构域契合，并与结合位点周围的残基广泛相互作用。它以浓度依赖的方式与PKC结合，解离常数KD为28.84±3.95μM。PKC-CGA复合物是稳定的，三维结构的扭曲最小，并且在模拟期间维持配体与受体之间的氢键。用CGA刺激的细胞导致12.1±0.56%的PKC从细胞质转移到质膜。它扰乱细胞周期并使癌细胞停滞在G1期，S期减少。绿原酸对MDAMB-231和MCF-7细胞分别以剂量依赖的方式杀死癌细胞，IC50分别为75.88±4.54μg/ml和52.5±4.72μg/ml。通过AO/EtBr染色和基因组DNA降解呈现梯状模式表明，它可诱导癌细胞凋亡。癌细胞中的凋亡涉及线粒体途径，这由线粒体电位降低和细胞色素C释放到细胞质中得到支持。因此，当前的研究已确定PKC是CGA所观察到的抗癌作用的重要信号分子，并为设计更好的CGA类似物以提高对恶性肿瘤的抗癌潜力提供了动力。
