Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a toxin, named after the plant genus Plumbago from which it was first isolated in 1968 (1). Since its discovery there have been a wide variety of publications describing its effects on fertility, hyperlipedaemia (high cholesterol) and its use as an anti-bacterial. More recently, there have been multiple efforts to synthesise derivatives and analogues of plumbagin in order to increase its potential as an anti-cancer agent.
Resistance of tumour cells to apoptosis is a major obstacle to be overcome when treating cancerous malignancies; however plumbagin has been shown to induce apoptosis in several cancer cell lines, including those of the breast, ovary and lung. Gomathinayagam et al treated lung cancer cell lines with plumbagin, and demonstrated that this led to a marked decrease in expression levels of the transcription factor NF-κB (an inhibitor of apoptosis) and its downstream target Bcl2 (2). In addition they showed plumbagin to effectively inhibit proliferation of lung cancer cell lines, whilst exerting little effect on a control (BEAS-2B, a normal lung epithelial cell line). Ahmad et al produced similar data in breast cancer cells, showing plumbagin to induce apoptosis with a concomitant inactivation of Bcl2 and the DNA-binding activity of NF-κB (3).
In a more recent study, Sung et al investigated the effects of a plumbagin analogue in suppressing bone loss, which is one of the major complications associated with advanced cancers. Bone loss can occur as the result of metastatic lesions, or can be a side effect of some cancer drugs. It can also arise due to the stimulation of osteoclastic activity following the release of various factors from cancer cells, for example production of IL1, IL6 and IL11 by breast cancer cells is known to increase production of RANKL (Receptor Activator of NF-κB Ligand), leading to osteoclastogenesis and a subsequent increase in bone dissolution and resorption. The authors of this study inoculated mice with the breast cancer cell line MDA-MB-231 then quantified osteolysis in bone metastases following treatment with plumbagin as compared to a vehicle control. Plumbagin was shown to significantly decrease breast cancer-induced bone loss in the mice (4).
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Plumbagin (IL17 Inhibitor)
Plumbagin is just one of a huge diversity of natural products that have been investigated as anti-tumour therapies (5). Research is on-going in order to increase our understanding of the full potential of such compounds, and to establish synthetic routes to produce the next generation of more potent products with greater bioavailability.
Written by Emma Easthope
