The Effects of A Natural Product Andrographolide in Cancer Cells
Date Issued
2015
Date
2015
Author(s)
Ho, Ya-Yeh
Abstract
Natural compounds are small molecules that are produced by bio-organisms. Many natural products are endowed with electrophilic functional groups that covalently modify nucleophilic residues in specific protein targets. The natural product, andrographolide, is the major active principle isolated from the plant Andrographis paniculata Nees, has been shown with a broad range of biological activities, such as anti-inflammatory, anticancer, and antibacterial. Moreover, both the use of andrographolide in traditional medicine and toxicity data in animals suggest the safety in andrographolide for diversiform clinical conditions. Although some of its anti-inflammatory effects have been investigated, little is known about the mechanisms underlying the pharmacological action of andrographolide. NF-κB transcription factors are critical regulator of apoptosis and proliferation. NF-κB is frequently constitutively activated in patients with chronic inflammatory conditions such as cancer. Accordingly, NF-κB controls multiple genes involved in human diseases rendering the NF-κB signaling pathway a target for therapy. We analyzed the structure of andrographolide and predicted that andrographolide may be a covalent drug. Andrographolide can be attacked by the cysteine residues of the protein through Michael addition to form the covalent bonds. We developed a new methodology by generating anti-andrographolide polyclonal antibody for target identification. Then, we demonstrated that the NF-κB could be modified by andrographolide after the cells were treated with andrographolide. In the TNF-α induced NF-κB activation model, we found that the NF-κB translocation from the cytoplasm to the nucleus can be inhibited in cervical cancer cells. Therefore, we surmised that some cysteine residues of the NF-κB are crucial for the NF-κB translocation and activation. On the other hand, we also showed that the YB-1 could be modified by andrographolide after the cells were treated with andrographolide. In the cisplatin induced YB-1 activation model, we found that the YB-1 translocation from the cytoplasm to the nucleus can be inhibited in pulmonary adenocarcinoma cells. In the TGF-β1 induced YB-1 activation model, overexpression of YB-1 could be inhibited and EMT-regulating genes could be downregulated, when the cells treated with andrographolide. A potent motility inhibitory effect of andrographolide has been demonstrated in pulmonary adenocarcinoma cells.
Subjects
Andrographolide
covalent drug
Michael addition
NF-κB；YB-1
SDGs
Type
thesis
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