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J Asian Nat Prod Res. 2004 Sep;6(3):155-66.

Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesis.

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Department of Pharmaceutical Science, Heilongjiang University, Harbin 150080, China.


Shikonin, isolated from the plant Lithospermum erythrorhizon Sieb. ET Zucc, inhibited tumor cell growth and induced cell death in various tumor cells, with 50% growth inhibition of human cervical cancer cells, HeLa, at 18.9 +/- 1.1 mumol L-1. Treated with 40 mumol L-1 shikonin, HeLa cells underwent marked apoptotic morphological changes such as a round shape, membrane blebbing and apoptotic bodies derived from the fragmented nuclei. Another hallmark of apoptosis, DNA fragmentation, was observed by gel electrophoresis. Shikonin (10 mumol L-1) significantly blocked the transition from G1 to S phase in the HeLa cell cycle. Pan-caspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK) or caspase-8 inhibitor (Z-IETD-FMK) effectively inhibited shikonin-induced cell death, while caspase-1 inhibitor (Ac-YVAD-CMK) and caspase-9 inhibitor (Z-LEHD-FMK) failed to affect cell death. Caspase-3 activity significantly increased within 12 h after shikonin treatment. Reduced expression of inhibitor of caspase-activated deoxyribonuclease (ICAD) after exposure to shikonin for 12 h suggests the resultant activation of caspase-activated deoxyribonuclease (CAD), leading to apoptosis.

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