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β-Hydroxyisovalerylshikonin promotes reactive oxygen species production in HCT116 colon cancer cells, leading to caspase-mediated apoptosis

Dilshara, Matharage Gayani, Karunarathne, Wisurumuni Arachchilage Hasitha Maduranga, Molagoda, Ilandarage Menu Neelaka, Kang, Chang-Hee, Jeong, Jin-Woo, Choi, Yung Hyun, Kim, Gi-Young
Revista Brasileira de Farmacognosia 2018 v.28 no.3 pp. 344-351
acetylcysteine, apoptosis, caspase-8, caspase-9, colorectal neoplasms, glutathione, mitochondria, neoplasm cells, reactive oxygen species, therapeutics, viability
Although β-hydroxyisovalerylshikonin is suggested as a potential therapeutic agent for preventing various cancers, the underlying molecular mechanisms are not completely understood. In the present study, we investigated whether β-hydroxyisovalerylshikonin enhances apoptosis by triggering reactive oxygen species production in colon cancer HCT116 cells. β-Hydroxyisovalerylshikonin significantly inhibited the viability of HCT116 cells with maximum inhibition at 4μM. Furthermore, treatment with β-hydroxyisovalerylshikonin subsequently increased sub-G1 cells and annexin-V+ cell population. Additionally, pretreatment with the caspase-8 inhibitor, z-IETD-fmk, and the caspase-9 inhibitor, z-LETD-fmk, significantly decreased β-hydroxyisovalerylshikonin-induced apoptosis, suggesting that β-hydroxyisovalerylshikonin promotes apoptosis through both the intrinsic and the extrinsic apoptotic pathways by activating caspase-8 and caspase-9. We also found that mitochondria played an important role in β-hydroxyisovalerylshikonin-mediated apoptosis via the intrinsic pathway. Accordingly, β-hydroxyisovalerylshikonin-induced reactive oxygen species production was evident after treatment with β-hydroxyisovalerylshikonin, and pretreatment with reactive oxygen species inhibitors, N-acetyl-l-cysteine and glutathione, significantly decreased β-hydroxyisovalerylshikonin-induced reactive oxygen species production, resulting in inhibition of apoptosis, which suggests that ROS generation is required for β-hydroxyisovalerylshikonin-mediated apoptosis. Taken together, these results demonstrated that the apoptotic effect of β-hydroxyisovalerylshikonin is enhanced in colon cancer HCT116 cells via reactive oxygen species generation and triggering of the caspase pathways, indicating that β-hydroxyisovalerylshikonin has potential as a therapeutic in the treatment of colon cancers.