Anti-cancerous effect of cis-khellactone from Angelica amurensis through the induction of three programmed cell deaths

Abstract

Angelica amurensis has traditionally been used to treat various medical problems. In this report, we introduce cis-khellactone as a new anti-cancer agent, which was isolated from the chloroform soluble fraction of the rhizomes of Angelica amurensis. Its anti-cancerous effect was at first tested in MCF7 and MDA-MB-231 breast cell lines, in which MCF7 is well known to be resistant to many anti-cancer drugs; MCF10A normal breast cell line was used as a control. In vitro experiments showed that cis-khellactone suppressed cell growth and proliferation at a relatively low concentrations (<5 μg/ml) and decreased cell viability at high concentrations (>10 μg/ml) in both cancer cell lines in a time- and concentration-dependent manner. This anti-cancerous effect was also checked in additional 16 different types of normal and cancer cell lines. Cis-khellactone treatment significantly suppressed cell proliferation and enhanced cell death in all tested cancer cell lines. Furthermore, Western blot analysis showed that cis-khellactone induced three types of programmed cell death (PCD): apoptosis, autophagy-mediated cell death, and necrosis/necroptosis. Cis-khellactone concentration-dependently decreased cell viability by increasing the level of reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), which are related to all three types of PCD. Mitochondrial fractionation data revealed that cis-khellactone induced the translocation of BAX and BAK into mitochondria as well as the overexpression of VDAC1, which probably accelerates MMP disruption and finally cell death. Importantly, our extended in vivo studies with xenograft model further confirmed these findings of anti-cancerous effects and showed no harmful effects in normal tissues, suggesting that there would be no side effects in humans.

MS275 as Class I HDAC inhibitor displayed therapeutic potential on malignant ascites by iTRAQ-based quantitative proteomic analysis

“…Proteins related to necroptosis, apoptosis and ferroptosis had higher expression in MS275 treated S180 cells. Specifically, PARP1, H2AX, VDAC1 and STAT2 could promote necroptosis [ 29 – 32 ]; PAPR1, LMNB2 and AIFM1 could promote apoptosis [ 33 – 35 ]; HMOX1 could promote ferroptosis [ 36 ]. This was also supported by our cell apoptosis assay data.…”

A comprehensive review of antitumor properties of Angelica species and their antitumor‐responsible constituents and the underlying molecular mechanisms involved in tumor inhibition

“…To date, various species of the Angelica genus have been reported to possess antitumor properties including, Angelica acutiloba (Roh et al, 2012), Angelica atropurpurea (Kontogiorgis et al, 2012), Angelica archangelica , Angelica dahuria (Dong et al, 2021; Kim et al, 2007), Angelica edulis (Wang, Sun, et al, 2014; Wang, Xiao, et al, 2014), Angelica keiskei ( Jeong et al, 2011), Angelica glauca (Kumar et al, 2022), Angelica japonica (Kimura et al, 2008), Angelica amurensis (Jung et al, 2018), Angelica polymorpha (Rahman et al, 2016), Angelica sylvestris (Raal et al, 2022), Angelica shikokiana (Mira et al, 2017), Angelica sinensis , and Angelica gigas (Kim et al, 2022) (Figure 1). Through extensive literature study about Angelica species, specifically focusing on A .…”

Crucial role of Ca2+/CN signalling pathway in the antifungal activity of disenecioyl‐cis‐khellactone against Botrytis cinerea

“…6 DK is an angular pyranocoumarin of the khellactone group, while some khellactone-type coumarins possess multiple bioactivities, including anti-HIV, anti-cancer, anti-inflammatory, anti-diabetic, anti-hypertensive, and antiosteoclastogenic activities. [7][8][9][10][11][12] Some activities of these compounds were considered to be related to calcium ion (Ca 2+ ) and Ca 2+ signalling pathway. [12][13][14][15][16] As a second messenger in both mammals and fungi, Ca 2+ controls the expression patterns of its signalling pathway and has essential roles in cell survival.…”

“…In addition, DK displayed strong antifungal activity against B. cinerea in vitro (EC 50 = 11.0 μg mL −1 ), which indicated its potential as a lead compound for the development of new fungicides against B. cinerea 6 . DK is an angular pyranocoumarin of the khellactone group, while some khellactone‐type coumarins possess multiple bioactivities, including anti‐HIV, anti‐cancer, anti‐inflammatory, anti‐diabetic, anti‐hypertensive, and anti‐osteoclastogenic activities 7–12 . Some activities of these compounds were considered to be related to calcium ion (Ca 2+ ) and Ca 2+ signalling pathway 12–16 …”