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International Journal of Molecular... Sep 2022Combined cisplatin-gemcitabine treatment causes rapid resistance development in patients with advanced urothelial carcinoma. The present study investigated the potential...
Combined cisplatin-gemcitabine treatment causes rapid resistance development in patients with advanced urothelial carcinoma. The present study investigated the potential of the natural isothiocyanates (ITCs) allyl-isothiocyanate (AITC), butyl-isothiocyanate (BITC), and phenylethyl-isothiocyanate (PEITC) to suppress growth and proliferation of gemcitabine- and cisplatin-resistant bladder cancer cells lines. Sensitive and gemcitabine- and cisplatin-resistant RT112, T24, and TCCSUP cells were treated with the ITCs, and tumor cell growth, proliferation, and clone formation were evaluated. Apoptosis induction and cell cycle progression were investigated as well. The molecular mode of action was investigated by evaluating cell cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins A and B) and the mechanistic target of the rapamycin (mTOR)-AKT signaling pathway. The ITCs significantly inhibited growth, proliferation and clone formation of all tumor cell lines (sensitive and resistant). Cells were arrested in the G2/M phase, independent of the type of resistance. Alterations of both the CDK-cyclin axis and the Akt-mTOR signaling pathway were observed in AITC-treated T24 cells with minor effects on apoptosis induction. In contrast, AITC de-activated Akt-mTOR signaling and induced apoptosis in RT112 cells, with only minor effects on CDK expression. It is concluded that AITC, BITC, and PEITC exert tumor-suppressive properties on cisplatin- and gemcitabine-resistant bladder cancer cells, whereby the molecular action may differ among the cell lines. The integration of these ITCs into the gemcitabine-/cisplatin-based treatment regimen might optimize bladder cancer therapy.
Topics: Apoptosis; Carcinoma, Transitional Cell; Cell Line, Tumor; Cisplatin; Cyclin-Dependent Kinases; Cyclins; Deoxycytidine; Humans; Isothiocyanates; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Urinary Bladder Neoplasms; Gemcitabine
PubMed: 36232303
DOI: 10.3390/ijms231910996 -
Pharmaceutics Sep 2023Cancerous cells are characterised by their ability to invade, metastasise, and induce angiogenesis. Tumour cells use various molecules that can be targeted to reverse...
Combination of Phenethyl Isothiocyanate and Dasatinib Inhibits Hepatocellular Carcinoma Metastatic Potential through FAK/STAT3/Cadherin Signalling and Reduction of VEGF Secretion.
Cancerous cells are characterised by their ability to invade, metastasise, and induce angiogenesis. Tumour cells use various molecules that can be targeted to reverse these processes. Dasatinib, a potent Src inhibitor, has shown promising results in treating hepatocellular carcinoma (HCC) in vitro and in vivo. However, its effectiveness is limited by focal adhesion kinase (FAK) activation. Isothiocyanates, on the other hand, are phytochemicals with broad anticancer activity and FAK inhibition capabilities. This study evaluated the synergistic effect of dasatinib and phenethyl isothiocyanate (PEITC) on HCC. The combination was tested using various assays, including MTT, adhesion, scratch, Boyden chamber, chorioallantoic membrane (CAM), and yolk sac membrane (YSM) assays to evaluate the effect of the drug combination on HCC metastatic potential and angiogenesis in vitro and in vivo. The results showed that the combination inhibited the adhesion, migration, and invasion of HepG2 cells and reduced xenograft volume in the CAM assay. Additionally, the combination reduced angiogenesis in vitro, diminishing the growth of vessels in the tube formation assay. The inhibition of FAK/STAT3 signalling led to increased E-cadherin expression and reduced VEGF secretion, reducing HCC metastatic potential. Therefore, a combination of PEITC and dasatinib could be a potential therapeutic strategy for the treatment of HCC.
PubMed: 37896150
DOI: 10.3390/pharmaceutics15102390 -
Biomedicine & Pharmacotherapy =... Oct 2021Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased...
Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased inflammation, all of which contribute to renal injury. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate well known for its antioxidant and anti-inflammatory effects, yet its reno-preventive effects against DN has not been investigated. The current study looked into the in vivo reno-protective effects of PEITC in STZ-induced DN in rats. PEITC (3, 10 and 30 mg/kg) was administered orally for 8 weeks post DM establishment. PEITC treatment significantly improved kidney and liver functions, renal histopathological features, tissue fibrosis, macrophage infiltration and blood glucose levels compared to DN control. Mechanistically, PEITC treatment alleviated DN-induced renal damage via modulating glycation and oxidative stresses and inflammatory response. As such, PEITC activated glyoxalase 1 (GLO1) that induced a retraction in renal tissue expression of advanced glycation end products (AGEs) and its receptor (RAGE). PEITC activated nuclear erythroid 2-related factor 2 (Nrf2) and increased expression of its downstream targets, hemeoxygenase-1 (HO-1) and gamma glutamate-cysteine (γ-GCS). Additionally, PEITC treatment decreased the expression of Nrf2 repressor protein, keap1. The anti-inflammatory effect of PEITC was driven, at least in part, via reducing the NLRP3 inflammasome activation as indicated by down regulation of NLRP3, TXNIP, capsase-1 and IL-1β, TNF-alpha and IL-6. In conclusion; PEITC attenuated DN progression in a dose dependent manner mainly via interruption of AGE/RAGE and NLPR3/TXNIP/NrF2 crosstalk.
Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibrosis; Glutamate-Cysteine Ligase; Glycation End Products, Advanced; Heme Oxygenase (Decyclizing); Inflammation; Isothiocyanates; Kelch-Like ECH-Associated Protein 1; Lactoylglutathione Lyase; Liver; Macrophages; Male; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Signal Transduction; Streptozocin; Up-Regulation; Rats
PubMed: 34215478
DOI: 10.1016/j.biopha.2021.111666 -
Frontiers in Pharmacology 2023Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target...
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target key pathways synergistically to reduce tumour growth. Isothiocyanates have been shown to possess anticancer potential and to complement the anticancer activity of other compounds. This study aimed to investigate the potential of phenethyl isothiocyanate (PEITC) to synergise with dasatinib, improving its anticancer potential in HCC. MTT, 3D spheroids and clonogenic assays were used to assess the combination anti-tumour effect , whereas a murine syngeneic model was employed to evaluate the combination efficacy . DCFDA staining was employed to evaluate the production of reactive oxygen species (ROS), while flow cytometry and Western blot assays were used to elucidate the molecular mechanism of the synergistic activiy. PEITC and dasatinib combination exhibited a synergistic effect and . The combination induced DNA damage and oxidative stress through the production of ROS, which led to the formation of a premature CDK1/Cyclin B1 complex associated with induction of mitotic catastrophe. Furthermore, ROS activated oxeiptosis, a caspase-independent form of programmed cell death. PEITC showed to enhance dasatinib action in treating HCC with increased production of ROS that induced cell cycle arrest followed by mitotic catastrophe, and to induce oxeiptosis. These results highlight the role that ITCs may have in cancer therapy as a complement of clinically approved chemotherapeutic drugs.
PubMed: 37860118
DOI: 10.3389/fphar.2023.1264032 -
Frontiers in Immunology 2022Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells.
OBJECTIVE
Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells.
MATERIALS AND METHODS
Based on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database.
RESULTS
We obtained 50 hub target genes for CD4 T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19 B cells and 15 target pathways for CD4 T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways.
CONCLUSION
We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.
Topics: Humans; Transcriptome; Drug Repositioning; Leukocytes, Mononuclear; Gene Expression Profiling; Multiple Sclerosis; Fingolimod Hydrochloride; Phosphatidylinositol 3-Kinases
PubMed: 36341423
DOI: 10.3389/fimmu.2022.1020721 -
Experimental Hematology & Oncology Feb 2014Combination of phenethyl isothiocyanate (PEITC) and paclitaxel (taxol) has been shown to work synergistically to increase apoptosis and cell cycle arrest in breast...
Combination of phenethyl isothiocyanate (PEITC) and paclitaxel (taxol) has been shown to work synergistically to increase apoptosis and cell cycle arrest in breast cancer cells. In this report, we further explored the mechanisms for the synergistic activity of PEITC and taxol in MCF7 and MDA-MB-231 (MB) breast cancer cell lines. By Western blotting analysis, treatment of MCF7 cells with both PEITC and taxol led to a 10.4-fold and 5.96-fold increase in specific acetylation of alpha-tubulin over single agent PEITC and taxol, respectively. This synergistic effect on acetylation of alpha-tubulin was also seen in MB cells. The combination of PEITC and taxol also reduced expressions of cell cycle regulator Cdk1, and anti-apoptotic protein bcl-2, enhanced expression of Bax and cleavage of PARP proteins. In conclusion, this study provided biochemical evidence for the mechanism of synergistic effect between the epigenetic agent PEITC and the chemotherapeutic agent taxol.
PubMed: 24495785
DOI: 10.1186/2162-3619-3-5 -
Cancer Prevention Research... Jan 20202-Phenethyl isothiocyanate (PEITC) is a natural product found as a conjugate in cruciferous vegetables. It has been reported to have preventative properties against lung... (Randomized Controlled Trial)
Randomized Controlled Trial
2-Phenethyl isothiocyanate (PEITC) is a natural product found as a conjugate in cruciferous vegetables. It has been reported to have preventative properties against lung cancer and to inhibit metabolic activation of tobacco carcinogens. In this study, we evaluated the ability of PEITC to influence the metabolism of the human carcinogen 1,3-butadiene in current smokers in a phase II clinical trial with a crossover design. Urinary mercapturic acids of 1,3-butadiene were quantified at baseline and during PEITC treatment. Seventy-nine smokers were randomly assigned to one of two arms: PEITC followed by placebo or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Oral ingestion of PEITC increased urinary levels of BD-mercapturic acids (MHBMA and DHBMA) by 11.1% and 3.7%, respectively, but these increases were not statistically significant ( = 0.17 and 0.64, respectively). A much stronger effect was observed among subjects with the null genotype of both and : in these individuals, PEITC increased urinary levels of MHBMA by 58.7% ( = 0.004) and 90.0% ( = 0.001), respectively, but did not have a significant effect on urinary DHBMA. These results reveal a potentially protective effect of PEITC treatment with respect to the detoxification of 1,3-butadiene in cigarette smokers, specifically in those null for , and provide further evidence in support of stronger chemopreventive effects from consumption of dietary isothiocyanates in these individuals.
Topics: Administration, Oral; Adult; Anticarcinogenic Agents; Butadienes; Carcinogens; Cigarette Smoking; Feeding Behavior; Female; Genotyping Techniques; Glutathione Transferase; Humans; Isothiocyanates; Lung Neoplasms; Male; Middle Aged; Smokers
PubMed: 31771940
DOI: 10.1158/1940-6207.CAPR-19-0296 -
International Journal of Molecular... Feb 2019Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with...
Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of oxidative stress than regular cancer cells. Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells. However, this pro-oxidant role of PEITC in CSCs is poorly understood and is investigated here. In a HeLa CSCs model (hCSCs), the sphere-culture and tumorsphere assay showed significantly enriched ALDH CSCs from HeLa parental cells ( < 0.05). Aldefluor assay and cell proliferation assay revealed that PEITC treatments resulted in a reduced number of ALDH hCSCs in a concentration-dependent manner ( < 0.05). In the ROS assay, PEITC promoted oxidative stress in hCSCs ( ≤ 0.001). Using immunoblotting and flow cytometry techniques, we reported that PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein) (both, < 0.05). Furthermore, PEITC-treatment of hCSCs, prior to xenotransplantation in mice, lowered the in vivo tumor-initiating potential of hCSCs. In summary, PEITC treatment suppressed the proliferation of ALDH1 expressing cancer stem cells as well as key factors that are involved with drug-resistance, while promoting oxidative stress and apoptosis in hCSCs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Aldehyde Dehydrogenase 1 Family; Animals; Apoptosis; Cell Proliferation; HeLa Cells; Humans; Hyaluronan Receptors; Isoenzymes; Isothiocyanates; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Oxidative Stress; Reactive Oxygen Species; Retinal Dehydrogenase; Sp1 Transcription Factor; Spheroids, Cellular
PubMed: 30818757
DOI: 10.3390/ijms20051027 -
Food Science & Nutrition Jun 2021Accumulation of cholesterol-laden macrophage foam cells characteristic of early stage atherosclerotic lesions. Phenethyl isothiocyanate (PEITC) is a naturally occurring...
Protective effects of phenethyl isothiocyanate on foam cell formation by combined treatment of oxidized low-density lipoprotein and lipopolysaccharide in THP-1 macrophage.
Accumulation of cholesterol-laden macrophage foam cells characteristic of early stage atherosclerotic lesions. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate found in cruciferous vegetables that has reported a variety of activities including antioxidant and anti-inflammatory properties. However, the protective effect of PEITC on foam cell formation and its precise mechanism is not yet clear. Therefore, we investigated whether PEITC suppresses foam cell formation and regulates the expression of genes related to lipid accumulation, cholesterol efflux, and inflammation in THP-1 derived-macrophages. We exposed THP-1 derived-macrophages to oxidized low-density lipoprotein (ox-LDL) (20 μg/mL) and lipopolysaccharide (LPS) (500 ng/ml) to mimic foam cell formation. Here, PEITC downregulated the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), cluster of differentiation 36 (CD36), scavenger receptor A1 (SR-A1), and nuclear factor-κB (NF-κB), while upregulated ATP binding cassette subfamily A member 1 (ABCA1)/liver-X-receptor α (LXR-α)/peroxisome proliferator-activated receptor gamma (PPARγ) and sirtuin 1 (SIRT1) expression compared to co-treated with ox-LDL and LPS. Taken together, PEITC, at least in part, inhibits foam cell formation and reduces lipid accumulation in foam cells. Therefore, we suggest that PEITC may be a potential candidate for the treatment and prevention of vascular inflammation and atherosclerosis.
PubMed: 34136191
DOI: 10.1002/fsn3.2293 -
Experimental Biology and Medicine... Jan 2023Phenethyl isothiocyanate (PEITC), a secondary metabolite in Cruciferous plants, exerts chemopreventive and antioxidant effects. However, its therapeutic potential in...
Phenethyl isothiocyanate (PEITC), a secondary metabolite in Cruciferous plants, exerts chemopreventive and antioxidant effects. However, its therapeutic potential in cyclophosphamide (CP)-induced nephrotoxicity is not clear. So, we focused to research on the effect of PEITC against renal toxicity caused by CP and its relationship to the Nrf2 signaling mechanism. Thirty female Wistar albino rats were allocated to three groups: control ( = 10), CP ( = 10), and PEITC-pretreated group (150 µmol/kg b.w. orally; = 10). The antioxidant enzyme activities and levels of malondialdehyde (MDA), sirtuin 1 (SIRT1), glutathione-S-transferase (GST), nuclear factor E2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), serum urea, and creatinine (Cr) were measured. In the CP group, serum urea and Cr, MDA, and NF-κB levels have risen, and the activities of antioxidant enzymes and SIRT1, Nrf2, and GST levels have reduced significantly ( < 0.05). PEITC diminished levels of Cr, urea, MDA, and NF-κB while it enhanced antioxidant enzyme activities and GST, Nrf2, and SIRT1 levels significantly ( < 0.05). Pretreatment with PEITC ameliorated kidney tissue injury. The renal protective effect of the PEITC was supported by the histological analysis of the kidney. PEITC prevented CP-induced nephrotoxicity by decreasing oxidative damage through Nrf2 and SIRT1 activation and NF-κB inhibition. Therefore, we have suggested that PEITC may be a useful agent for protection against CP-induced renal injury.
Topics: Animals; Rats; NF-E2-Related Factor 2; NF-kappa B; Antioxidants; Sirtuin 1; Rats, Wistar; Cyclophosphamide; Kidney; Oxidative Stress
PubMed: 36598044
DOI: 10.1177/15353702221139206