Metabolic profiling study of shikonin's cytotoxic activity in the Huh7 human hepatoma cell line

Abstract

Shikonin and its enantiomer alkannin, which are natural products, have been extensively studied in vitro and in vivo for, among others, their antitumor activity. The investigation of the molecular pathways involved in their action is of interest, since they are not yet clearly defined. Metabolic profiling in cells can provide a picture of a cell's phenotype upon intervention, assisting in the elucidation of the mechanism of action. In this study, the cytotoxic effect of shikonin on a human hepatocarcinoma cell line was studied. Huh7 cells were treated with shikonin at 5 μM, and it was found that shikonin markedly inhibited cell growth. Metabolic profiling indicated alterations in the metabolic content of the cells and the culture media upon treatment, detecting the metabolic response of the cells. This study demonstrates the potential of metabolomics to improve knowledge on the mechanisms involved in shikonin's antitumor action.

Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin

“…Our group investigated the inhibition of c-MYC expression and transcriptional activity by shikonin as a novel mechanism for killing leukemia cells [9], and more recently, the cytotoxic activity of shikonin to the Huh7 cancer cell line by a metabolite profiling approach which could set a basis for the elucidation of their antitumor activity was investigated [13]. Shikonin has also been proposed as a novel dietary agent with great potential in breast cancer prevention [14] and has been found to act synergistically to potentiate doxorubicin-induced growth inhibition and apoptosis in vitro [15].…”

Broad blocking of MDR efflux pumps by acetylshikonin and acetoxyisovalerylshikonin to generate hypersensitive phenotype of malignant carcinoma cells

“…MCF7MX cells presented chemotoleration features for mitoxantrone cytotoxicity during both shikonin treatments even though BCRP pump activity was significantly (P < 0.001) blocked during the experiment time. Such behaviors may be attributed to alteration of metabolism pathways of cancer cells associated with energy consumption, chemotherapeutics metabolism and physicochemical inactivation of the hydroxyl naphthoquinones in this cell 36 , 38 . Our initial investigations demonstrated that chemosensitization and MDR-associated efflux blockage are less likely dependent on shikonin dosage volumes; such separate activities support the hypothesis that shikonins are uncompetitive pump blockers.…”

Naphthoquinones: A continuing source for discovery of therapeutic antineoplastic agents

“…STAT3 is a key mediator transferring extracellular signals into cell nucleus to regulate various cellular processes including proliferation, apoptosis, angiogenesis, and other biological activities. [23][24][25][26] The activation of STAT3 is through the phosphorylation of the Tyr705 residue in SH2 domain and contributes to carcinogenesis and tumor progression when the activation is aberrantly up-regulated. [27,28] Great efforts have been devoted to identify potent inhibitors that hold promise for suppressing STAT3 activation, of which a considerable proportion is comprised by various naphthoquinones.…”

“…Of interest is the performance of naphthoquinone scaffold in the development of selective STAT3 (signal transducer and activator of transcription 3) inhibitors. STAT3 is a key mediator transferring extracellular signals into cell nucleus to regulate various cellular processes including proliferation, apoptosis, angiogenesis, and other biological activities . The activation of STAT3 is through the phosphorylation of the Tyr705 residue in SH2 domain and contributes to carcinogenesis and tumor progression when the activation is aberrantly up‐regulated .…”