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PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
For this reason, the culture medium and the phosphate-buffered saline (PBS) used to rinse cells before trypsinization were also collected.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Adherent cells were harvested by trypsinization and combined with cells in the culture medium and PBS.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The entire sample was then centrifugated and resuspended in 500 µL of fresh medium.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Samples were stained with Guava ViaCount™ or Guava Nexin Reagent according to the manufacturer’s instructions.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The Guava ViaCount™ distinguishes viable and non-viable cells based on the differential permeabilities of two DNA-binding dyes.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The nuclear dye (in the graphs indicated as “Nucleated Cells” on the y-axis) differentiates nucleated cells from cellular debris, while the viability dye brightly stains dying cells (in the graphs indicated as “Viability” on the x-axis).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The number of viable cells in the sample was defined starting from the cell concentration (cells/μL) calculated by the flow cytometer instrument.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The monitoring of apoptosis activation was performed using Guava Nexin Reagent.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The reagent combines fluorescently labeled Annexin V (Annexin V-PE) and 7-Aminoactinomycin D (7-AAD).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Annexin V-PE, a calcium-dependent phospholipid-binding protein with a high affinity for phosphatidylserine (PS), is a membrane component early exposed on the external cell surface during apoptotic pathway stimulation (indicated in the graphs as “Annexin-V” on the x-axis).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Instead, late apoptotic/dead cells are recognized by 7-AAD.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
This fluorescent DNA intercalator is membrane-impermeant and excluded from live, healthy, and early apoptotic cells (indicated in the graphs as “Viability” on the y-axis).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Five hundred grams of dried and grounded plant material was extracted using 2 L of CH3OH 80% v/v.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The extract was filtered and dried in a rotary evaporator; the extraction procedure was repeated four times (24 h each) on the same plant material, obtaining 67.7 g of extract.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The extract (AUN) was suspended in 700 mL of water and subjected to liquid/liquid partition using in-series chloroform (CHCl3) or ethyl acetate (EtOAc).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Phytochemical extractions were performed using each solvent three times.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Three AUN-derived fractions were obtained: CHCl3 (FR1; yield: 0.33% w/w), EtOAc (FR2; yield: 8.8% w/w), and H2O (FR3; yield 70%).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The stock solutions for the bioassays of FR3 were prepared by solubilizing dried extracts in distilled H2O at an initial concentration of 20 mg/mL, while FR2 and FR3 were instead solubilized in DMSO 10% at the same initial concentration.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
FR1, FR2, and FR3 fractions were then diluted (1:1000) during the biological assays, leading both H2O and DMSO to a final concentration of 0.1% in the medium supplemented with FBS 15%.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Being the bioactivity localized in the FR2, 4 g of the fraction was suspended in 5 mL of water and injected in a medium-pressure liquid chromatography (MPLC) instrument (Reveleris, Büchi, Switzerland) using a reverse-phase stationary phase (40 g of C18 column).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
A gradient of water (solvent A) and methanol (solvent B) was used as an eluent.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The gradient was composed of an isocratic phase of 10 min (90% A and 10% B), a gradient from 90% A to 80% A in 1.1 min, an isocratic phase of 20 min (80% A and 20% B), a gradient from 80% A to 70% A in 1.1 min, an isocratic phase of 10 min (70% A and 30% B), a gradient from 70% A to 50% A in 1.1 min, an isocratic phase of 10 min (50% A and 50% B) a gradient from 50% A to 30% A in 1.1 min, an isocratic phase of 5 min (30% A and 70% B), a gradient from 30% A to 0% A in 1.1 min, an isocratic phase of 5 min (0% A and 100% B).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The flow rate was 20 mL/min, and the run length was 70 min.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Based on the chromatogram and UV–Vis absorbance signals at three wavelengths (UV1 = 254 nm, UV2 = 270 nm, and UV3 = 340 nm), FR2-derived fractions were collected and dried, obtaining a total of four FR2 subfractions (FR2-A, FR2-B, FR2-C, and FR2-D).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
An analogous preparation of FR2 was followed for its subfractions in the biological assays.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Being the bioactivity localized in the FR2-A, 879.8 mg of the fraction was suspended in the minimum amount of methanol and then subjected to size exclusion chromatography using a chromatography column (1800 mm × 25 mm) filled with 220 g of Sephadex (LH-20) and, as an eluent, methanol.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The flow rate was 0.4 mL/min.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The eluate in each tube was concentrated in a rotary evaporator, and a small quantity was used to perform thin-layer chromatography (TLC).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The stationary phase of the TLC used a silica gel matrix with a 254 nm florescent indicator (Sigma-Aldrich), while EtOH:MeOH:H2O (10:1.35:1) was used as the mobile phase.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
This latter was employed to acquire a first overview of the chemical composition of the fractions by UV–Vis light exposure, enabling us to group the most similar ones, obtaining 84 final fractions.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Excluding the fraction yielding less than 1 mg of material, 61 were tested in the bioassays.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The most active ones were phytochemically investigated compared to the inactive or weakly active ones, which were eluted immediately before or after.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
H NMR spectra were recorded at 25 °C on a Varian Inova instrument (equipped with a reverse triple resonance probe) operating at 600.13 MHz.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Each H NMR spectrum consisted of 256 scans (corresponding to 16 min) with a relaxation delay (RD) of 2 s, acquisition time of 0.707 s, and spectral width of 9595.8 Hz (corresponding to δ 16.0).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
All the H NMR spectra were uploaded onto Zenodo.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The UHPLC-MS analysis was run on a Waters ACQUITY ARC UHPLC/MS system consisting of a QDa mass spectrometer equipped with an electrospray ionization interface and a 2489 UV–Vis detector.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The detected wavelengths (λ) were 254 nm and 365 nm.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The analyses were performed on an XBridge BEH C18 column (10 × 2.1 mm i.d.,
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
particle size 2.5 µm) with an XBridge BEH C18 VanGuard Cartridge precolumn (5 mm × 2.1 mm i.d.,
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
particle size 1.8 µm).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The mobile phases were H2O (0.1% formic acid) (A) and MeCN (0.1% formic acid) (B).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Electrospray ionization in positive and negative modes was applied in the 50–1200 Da mass scan range.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The FR2-A subfractions were diluted to 100 µg/mL, and a volume of 3 µL was injected.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The samples were eluted with the following method: 20% B for one minute, followed by a gradient reaching 95% B in 3 min; 95% B was kept for 1 min; then the gradient reached 20% B in 0.2 min again; and 20% B was kept for 2 min.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
The flow rate was 0.8 mL/min.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Statistical analysis was performed using GraphPad Prism software 8.0.2, applying the appropriate statistical test.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Details are indicated below each figure.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
IC50 was instead calculated with the free “aatbioquest” tool (https://www.aatbio.com/tools/ic50-calculator, accessed on 11 April 2024).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Whole-cell protein lysates were prepared using NP40 buffer containing protease inhibitors (halt protease and phosphatase inhibitor cocktail; Thermo Fisher Scientific) and 1 mM of phenylmethylsulfonyl fluoride (Sigma-Aldrich, St. Louis, MI, USA).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Proteins were separated in SDS-PAGE (12%) and transferred onto nitrocellulose membranes.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Membranes were blocked by 5% skimmed milk, followed by incubation at 4 °C overnight with primary antibodies.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Primary antibodies against KIT (A4502; Dako, Glostrup, Denmark), phospo-KIT (3391; Cell Signaling, Danvers, MA, USA), PARP-1 (9542, Cell-Signaling), and actin (A1978; Sigma-Aldrich) were used.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
After rinsing, membranes were incubated with horseradish peroxidase-conjugated secondary antibody (Thermo Fisher Scientific) at room temperature for 2 h. After further rinsing, immunoreactive bands were visualized by enhanced chemiluminescence (BioRad, Hercules, CA, USA), and signals were captured and quantified using ChemiDoc (BioRad).
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Sigma-Aldrich supplied β-arbutin and gallic acid for the biological assays.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Selleck Chemicals supplied imatinib.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
2.5 × 10 cells were seeded in a 96-well culture plate the day before the treatment.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Cells were treated with FR2-A-derived fractions, and viability was analyzed 24 h after treatment.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Treatment was removed, and cells were incubated with MTT reagent (0.5 mg/mL) in a medium without serum for 2 h. At the end of the incubation, the MTT solution was removed carefully, and formazan crystals were dissolved in DMSO.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Absorbance was read at 492 nm using a TECAN spectrophotometer.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Peripheral blood lymphocyte (PBMC) isolation was performed as described .
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Briefly, PBMCs were isolated from blood samples of healthy donors (Buffy coat) using a density gradient centrifugation with Histopaque-1077.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Donors were healthy, non-smokers, and with no known exposure to genotoxic chemicals or radiation.
PMC11085211
Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors
Authorization for the use of human blood samples for research purposes was received from AUSL Bologna IT, S. Orsola-Malpighi Hospital.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Imatinib has been widely used in gastrointestinal stromal tumours and significantly improved the prognosis of GIST patients, but approximately half of patients develop acquired treatment resistance, highlighting the urgency for novel therapeutic strategies.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
A variety of bioinformatic tools and laboratory experiments, RNA sequencing, animal models and the thermal proteome profiling assay were employed to validate our findings and investigate the antitumour effects of β‐elemene.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
We found that imatinib‐resistant GIST was associated with negative regulation of ferroptosis activity, and inducing ferroptosis can enhance the sensitivity of resistant cells to imatinib.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Furthermore, we found that β‐elemene enhances imatinib sensitivity in imatinib‐resistant GIST cells through inducing ferroptosis.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Moreover, the combination treatment of β‐elemene and imatinib showed significantly increased antitumour efficacy, compared to each monotherapy, both in vitro and in vivo.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Mechanistically, β‐elemene specifically targets N6AMT1, inhibiting its transcriptional repression function and activating the nuclear factor erythroid 2‐related factor 2 (NRF2)‐HMOX1 signalling pathway to induce ferroptosis.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Β‐elemene can target N6AMT1 and promote ferroptosis by increasing the expression of NRF2 and HMOX1.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
These findings suggest β‐elemene as a prospective therapeutic strategy to improve the sensitivity of imatinib in gastrointestinal stromal tumours.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
l Imatinib resistance is associated with ferroptosis activity in GIST.l Combination of β‐elemene and imatinib effectively treats gastrointestinal stromal tumours both in vivo and in vitro.l β‐elemene promotes imatinib sensitivity in GIST through ferroptosis.l N6AMT1 is a potential target of β‐elemene.l β‐elemene targets N6AMT1 to promote imatinib sensitivity in imatinib‐resistant GIST cells via the NRF2/HMOX1 axis.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
l Imatinib resistance is associated with ferroptosis activity in GIST.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
l Combination of β‐elemene and imatinib effectively treats gastrointestinal stromal tumours both in vivo and in vitro.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
l β‐elemene promotes imatinib sensitivity in GIST through ferroptosis.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
l N6AMT1 is a potential target of β‐elemene.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
l β‐elemene targets N6AMT1 to promote imatinib sensitivity in imatinib‐resistant GIST cells via the NRF2/HMOX1 axis.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal mesenchymal malignancy of the gastrointestinal tract, with an estimated incidence of 10–20 per million population. ,
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
GISTs are mainly caused by mutations in KIT or PDGFRA.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Imatinib is a tyrosine kinase inhibitor targeting BCR‐ABL, KIT and PDGFR, which has a highly inhibitory effect on GISTs and has been approved as the first‐line treatment for KIT‐positive GISTs.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
However, about 50% of patients developed drug resistance after 2 years of treatment with imatinib.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Secondary mutations partly explained the resistance of imatinib in GISTs with secondary imatinib resistance, , while approximately 40% of patients with no secondary mutations. ,
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
There are limited treatment options available for those patients without secondary mutations.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
The overall efficacy of these therapies is poor.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Therefore, analysing the molecular mechanism of imatinib resistance is extremely urgent and must be characterised to improve the long‐term prognosis of GIST patients by devising novel therapies.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Resisting cell death is one of the most important characteristics of cancer cells, and it is also the main reason for drug resistance.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Ferroptosis is a non‐apoptotic form of cell death characterised by the accumulation of iron and lipid peroxidation, which has become an effective target of anti‐cancer therapy.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Recent evidence suggests that ferroptosis is related to cancer chemotherapy resistance, and induction of ferroptosis can reverse drug resistance. ,
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Ferroptosis can be induced by inhibiting ADP ribosylation factor 6 (ARF6) to activate active fatty acid synthase 4(ACSL4), thereby overcoming gemcitabine resistance in pancreatic cancer.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
In addition, the PARP inhibitor olaparib is used in combination with ferroptosis inducers to enhance the sensitivity of BRCAproficient ovarian cancer cells to olaparib by inhibiting solute carrier family 7 member 11 (SLC7A11)‐mediated GSH synthesis.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
These results indicate the possibility of utilising ferroptosis as a strategy to overcome therapeutic resistance.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
β‐elemene, a bioactive compound isolated from the Chinese herb Curcumae Rhizoma, exhibits a low‐toxicity and broad‐spectrum anticancer effect and is used in various cancer types.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Several studies have revealed that β‐elemene plays an antitumour role through different pathways, such as activating mitochondrial‐dependent pathways, inducing apoptosis or arresting the cell cycle.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
More interestingly, β‐elemene is used clinically for radiation sensitisation and chemotherapy of various tumours, and it can effectively reverse drug resistance. ,
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Previous studies reported that β‐elemene produces combinative effects with some chemotherapies, such as oxaliplatin and gefitinib. ,
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
It was reported that β‐elemene could induce ferroptosis in lung cancer and colorectal cancer (CRC).
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
The combined therapy of β‐elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
However, the role of β‐elemene in imatinib‐resistant GIST cells and the targets for β‐elemene are not fully illustrated.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
Therefore, systematic exploration of the combined application of β‐elemene with imatinib to achieve better therapeutic effects is of great clinical significance given the grim reality of GIST treatment.
PMC12390768
β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1
In this study, we aimed to investigate the role of ferroptosis in regulating imatinib resistance in GIST cells.