Induction of Apoptosis by Shikonin through Coordinative Modulation of the Bcl-2 Family, p27, and p53, Release of Cytochrome c, and Sequential Activation of Caspases in Human Colorectal Carcinoma Cells

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Abstract
Shikonin is a main constituent of the roots of Lithospermum erythrorhizon that has antimutagenic activity. However, its other biological activities are not well-known. Shikonin displayed a strong inhibitory effect against human colorectal carcinoma COLO 205 cells and human leukemia HL-60 cells, with estimated IC50 values of 3.12 and 5.5 μM, respectively, but were less effective against human colorectal carcinoma HT-29 cells, with an estimated IC50 value of 14.8 μM. Induce apoptosis was confirmed in COLO 205 cells by DNA fragmentation and the appearance of a sub-G1 DNA peak, which were preceded by loss of mitochondrial membrane potential, reactive oxygen species (ROS) generation, cytochrome c release, and subsequent induction of pro-caspase-9 and -3 processing. Cleavages of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor (DFF-45) were accompanied by activation of caspase-9 and -3 triggered by shikonin in COLO 205 cells. Here, we found that shikonin-induced apoptotic cell death was accompanied by upregulation of p27, p53, and Bad and down-regulation of Bcl-2 and Bcl-XL, while shikonin had little effect on the levels of Bax protein. Taken together, we suggested that shikonin-induced apoptosis is triggered by the release of cytochrome c into cytosol, procaspase-9 processing, activation of caspase-3, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by shikonin may provide a pivotal mechanism for its cancer chemopreventive action. Keywords: Shikonin; apoptosis; cytochrome c; caspase-9; caspase-3; poly-(ADP-ribose) polymerase; DNA fragmentation factor; caspase-activated deoxyribonuclease; Bcl-2; Bcl-XL

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