Shikonin Exerts Cytotoxic Effects in Human Colon Cancers by Inducing Apoptotic Cell Death via the Endoplasmic Reticulum and Mitochondria-Mediated Pathways

• Published in: Biomolecules & therapeutics Vol. 27; no. 1; pp. 41 - 47
• Main Authors: Han, Xia, Kang, Kyoung Ah, Piao, Mei Jing, Zhen, Ao Xuan, Hyun, Yu Jae, Kim, Hyun Min, Ryu, Yea Seong, Hyun, Jin Won
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Society of Applied Pharmacology 01.01.2019; 한국응용약물학회
• Subjects: Original; 약학; Human colon cancer; Mitochondria; Shikonin; Endoplasmic reticulum; Apoptosis
• ISSN: 1976-9148; 2005-4483; 2005-4483
• DOI: 10.4062/biomolther.2018.047

The apoptotic effects of shikonin (5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methylpent-3-enyl]naphthalene-1,4-dione) on the human colon cancer cell line SNU-407 were investigated in this study. Shikonin showed dose-dependent cytotoxic activity against SNU-407 cells, with an estimated IC₅₀ value of 3 µM after 48 h of treatment. Shikonin induced apoptosis, as evidenced by apoptotic body formation, sub-G₁ phase cells, and DNA fragmentation. Shikonin induced apoptotic cell death by activating mitogen-activated protein kinase family members, and the apoptotic process was mediated by the activation of endoplasmic reticulum (ER) stress, leading to activation of the PERK/elF2α/CHOP apoptotic pathway, and mitochondrial Ca²⁺ accumulation. Shikonin increased mitochondrial membrane depolarization and altered the levels of apoptosis-related proteins, with a decrease in B cell lymphoma (Bcl)-2 and an increase in Bcl-2-associated X protein, and subsequently, increased expression of cleaved forms of caspase-9 and -3. Taken together, we suggest that these mechanisms, including MAPK signaling and the ER-and mitochondria-mediated pathways, may underlie shikonin-induced apoptosis related to its anticancer effect.