β-Hydroxyisovaleryl-Shikonin Exerts an Antitumor Effect on Pancreatic Cancer Through the PI3K/AKT Signaling Pathway

Abstract

Pancreatic cancer (PC) is marked with a low survival rate and lack of recognized effective treatment strategy. We investigated the antitumor effect of β-hydroxyisovaleryl-shikonin (β-HIVS) on PC and the associated working mechanism. Cell toxicity was determined using Cell Counting Kit-8 (CCK-8) assay. Acridine Orange/Ethidium Bromide (AO/EB) double-fluorescent staining assay accompanied by flow cytometry was utilized to estimate cell apoptosis. Cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential were all evaluated using flow cytometry. Transwell and wound healing assays were performed to evaluate cell migration and invasion. Protein expression was analyzed by Western blots. A xenograft mouse model was employed to determine the antitumor effect of β-HIVS in vivo. PC cell viability gradually decreased with increasing β-HIVS while apoptosis was enhanced together with cell-cycle blockage in the G0–G1 phases. β-HIVS induced mitochondrial dysfunction, ROS production, and DNA damage and inhibited the invasive and migratory ability of PC cells. We further confirmed the suppression of EMT and PI3K/AKT pathways as underlying mechanisms. The mouse model treated with the increasing dose of β-HIVS displayed decreased tumor growth rate, along with increased apoptosis. Thus, β-HIVS exerts antitumor effects on PC through inducing apoptosis, ROS production, decreasing mitochondrial membrane potential, and suppressing signal pathways, such as PI3K/AKT. In summary, β-HIVS might be a promising strategy for PC treatment.

Honokiol and Alpha-Mangostin Inhibit Mayaro Virus Replication through Different Mechanisms

“…Cytotoxicity analysis revealed that Sanguinarine chloride and (R)-Shikonin had considerable toxic effects for all doses and incubation times tested. These findings are consistent with previous reports of these compounds’ high cytotoxicity in several cancer cell lines, supporting their possible use as antitumoral drugs [ 30 , 31 , 32 , 64 ]. On the other hand, Fisetin, Honokiol, Tanshinone IIA, and α-Mangostin were well-tolerated at doses of 5 or 10 μM in the tested cell lines.…”

Honokiol and alfa-Mangostin inhibit Mayaro virus replication by stimulating the type I interferon pathway

“…Cytotoxicity analysis revealed that Sanguinarine chloride and (R)-Shikonin had considerable toxic effects for all doses and incubation times tested. These findings are consistent with previous reports of these compounds’ high cytotoxicity in several cancer cell lines, supporting their possible use as antitumoral drugs [30-32,64]. On the other hand, Fisetin, Honokiol, Tanshinone IIA and α-Mangostin were well-tolerated at doses of 5 or 10 μM in the tested cell lines.…”

Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression

“…One point we should note is that β-HIVS might also exert anticancer effects through the inhibition of tyrosine kinases such as v-Src, EGFR, or VEGFR2 [10,17]. PI3K/AKT signaling has also been reported as a signal involved in the inhibitory effect on tumor growth of β-HIVS [18,19]. Thus, future studies are required to investigate if the effect of β-HIVS on tumor growth inhibition with reduced EpCAM expression depends on the reduction in dUTPase alone.…”