Biomol Ther.  2019 Jan;27(1):41-47. 10.4062/biomolther.2018.047.

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

• Han X
• Kang KA
• Piao MJ
• Zhen AX
• Hyun YJ
• Kim HM
• Ryu YS
• Hyun JW

• KMID: 2432065
• DOI: http://doi.org/10.4062/biomolther.2018.047

Abstract

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.

Keyword

Shikonin; Human colon cancer; Apoptosis; Mitochondria; Endoplasmic reticulum

MeSH Terms

Apoptosis
bcl-2-Associated X Protein
Caspase 9
Cell Death*
Cell Line
Colon*
Colonic Neoplasms*
DNA Fragmentation
Endoplasmic Reticulum*
Extracellular Vesicles
Humans*
Inhibitory Concentration 50
Lymphoma, B-Cell
Mitochondria
Mitochondrial Membranes
Protein Kinases
Caspase 9
Protein Kinases
bcl-2-Associated X Protein