Shikonin is a natural naphthoquinone compound and has demonstrated potent anticancer activities; however, the underlying molecular mechanisms remained elusive. Here we report that Shikonin inhibited the growth of a wide range of human cancer cell lines, illustrating a broad anticancer effect. Mechanistically, we show that Shikonin arrested the cell cycle at the G2/M phase, inhibited the ERK-dependent cell growth signal, and induced cell death in both P53 wild type and mutant cancer cells, which collectively contributed to the growth inhibitory effect of Shikonin. A pan-apoptosis inhibitor largely suppressed Shikonin-induced cell death, suggesting an important role of apoptosis in this process. Intriguingly, Shikonin also activated autophagy and inhibition of autophagy by depleting critical autophagic genes further increased Shikonin-induced cell death, indicating a protective role of autophagy. In uncovering the molecular mechanisms underlying these effects of Shikonin, we found that Shikonin induced a robust upregulation of P21 independent of the P53 status, upregulated autophagy genes, as well as inhibited expression of genes required for cell growth. Using mouse tumor models, we confirmed the strong anticancer effect of Shikonin in vivo. Together, our data reveal a broad range of pharmacological functions of Shikonin, involving simultaneous growth inhibition, cell cycle arrest, autophagy activation and apoptosis induction through regulating expression of critical genes involved in these pathways. Our study may facilitate the development of Shikonin in cancer therapy as a single agent or in combination with other anticancer therapies.

Investigation of the seeds of Thevetia peruviana resulted in the isolation of 15 new (2–16) and 18 known (1 and 17–33) cardiac glycosides. Eight 19-nor-cardenolides (1–8), including two rare 19-nor-10-hydroperoxycardenolides, were obtained from T. peruviana for the first time. All the structures were characterized by NMR spectroscopy and chemical derivatization. The inhibitory effects of cardiac glycosides 1–33 against three cancer cell lines (human lung cancer cells, P15; human gastric cancer cells, MGC-803; and human pancreatic cancer cells, SW1990) and one normal hepatocyte cell line, LO2, were evaluated, and a preliminary structure–activity relationship is discussed. In addition, cardiac glycosides 1, 22, 26, and 28 were evaluated for their apoptosis-inducing activities in MGC-803 cells, showing IC50 values in the range 0.02–0.53 μM.

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Seven new coumarin analogues (1, 2, and 4−8), together with ten known analogues (3, 9−17), were isolated from the air-dried pericarp of Citrus grandis. The structures of these compounds were determined by HR-ESI-MS, UV/vis, and 1D-and 2D-NMR spectra. Meanwhile, the hepatoprotective activities of all these coumarins were evaluated by MTT assays using the D-galactosamine-induced LO2 cell injury model. The results show that compounds 3 and 4 exhibited the strongest hepatoprotective activities. Moreover, compounds 3 and 4 suppressed increases in the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in D-galactosamine-treated LO2 cells, further confirming the hepatoprotective effects of these compounds. Mechanistically, compounds 3 and 4 increased the activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the level of malondialdehyde (MDA) in injured LO2 cells induced by D-galactosamine. These findings shed light on a better understanding of the hepatoprotective effect of Citrus grandis, providing novel insights into the development of coumarin-based hepatoprotective drugs in the future.

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