Cancer: Sarcoma-180, lung, melanoma, leukemia
Action: Anti-inflammatory, inhibits angiogenesis, MDR
Shiunko is a Kampo herbal ointment often used for the treatment of burns in Japan. It is mainly isolated from the root of Lithospermum erythrorhizon (Siebold & Zuccarini), which had been used for treating tumors and inflammation in China since the 5th century. The naphthoquinone pigment shikonin is the most important pharmacologically active substance in the dried root of Lithospermum erythrorhizon. In traditional Chinese medicine root extracts of Lithospermum erythrorhizon have been used to treat macular eruption, measles, sore throat, carbuncles, and burns (Chen et al., 2002). The anti-tumor effect of shikonin was first evidenced by its activity against murine sarcoma-180 (Sankawa et al., 1977).
Melanoma
It has been reported that shikonin, the main chemical ingredient of L. erythrorhizon is a novel inhibitor of angiogenesis. Angiogenesis is critical for tumor growth and inflammation. It inhibited tumor necrosis factor-alpha-induced and B16 melanoma-induced angiogenesis in mice and normal developmental angiogenesis in the yolk-sac membranes of chick embryos. Shikonin also inhibited proliferation and migration of endothelial cells in culture and network formation by endothelial cells on Matrigel in vitro. The dose-responsive study suggests that the mechanism of this inhibitory effect on angiogenesis involves the prevention of network formation by endothelial cells via blocking integrin alpha v beta 3 expression (Hisa et al., 1998).
Anti-inflammatory
Shikonin also reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. It has been found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions.
Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent (Lu et al., 2011).
Leukemia, MDR
Shikonin has a strong cytotoxic effect on a wide variety of cancer cell lines, especially different types of leukemia and several known MDR cell lines. Microarray-based gene expression analysis of U937 leukemia cells suggested that the cytotoxicity of shikonin is based on the disruption of normal mitochondrial function, overproduction of ROS, inhibition of cytoskeleton formation, and finally induction of cell-cycle arrest and apoptosis. These effects were validated using in vitro cell culture experiments exploiting the specific natural fluorescence of shikonin and thereby identifying the possible primary cellular mechanism of shikonin's cytotoxicity (Wiench et al., 2012).
Lung Cancer
To better understand the anti-metastatic role of shikonin in lung cancer, the effect of shikonin on lung cancer cell proliferation was investigated, as well as its adhesion to extracellular matrices (ECM), migration and invasion in non-small-cell lung cancer A549 cells. Taken together, findings provide new evidence that shikonin suppresses lung cancer invasion and metastasis by inhibiting integrin β1 expression and the ERK1/2 signaling pathway. Integrin β1 facilitates cancer cell adhesion, migration and metastasis by activating intracellular signaling pathways including the ERK and PI3K signaling pathways, and it is in this way that shikonin exerts its anti-cancer activity (Wang et al., 2013).
MDR
Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anti-cancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Shikonin was investigated for its ability as an inducer of cancer drug resistance. Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. After an 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross-resistance to shikonin analogs and other anti-cancer agents. These merits make shikonin and its analogs potential candidates for cancer therapy with the advantages of avoiding induction of drug resistance and bypassing existing drug resistance (Wu et al., 2013).
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