scholarly journals Tryptophan metabolism induced by TDO2 promotes prostatic cancer chemotherapy resistance in a AhR/c-Myc dependent manner

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fan Li ◽  
Zhenyu Zhao ◽  
Zongbiao Zhang ◽  
Yan Zhang ◽  
Wei Guan
Keyword(s):  
Cancer Treatment ◽  
Cell Lines ◽  
Prostatic Cancer ◽  
Nuclear Translocation ◽  
Metabolic Reprogramming ◽  
Dependent Manner ◽  
Cell Bank ◽  
Slc Transporters ◽  
Tumor Tissues

Abstract Background Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood. Materials and methods Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6 ~ 8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments. Result Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2, 3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment. Conclusion Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.

scholarly journals Tryptophan Metabolism Induced by TDO2 Promotes Prostatic Cancer Chemotherapy Resistance in a Ahr/C-Myc Dependent Manner

2021 ◽  
Author(s):  
Fan Li ◽  
ZHENYU Zhao ◽  
ZONGBIAO Zhang ◽  
YAN ZHANG ◽  
WEI GUAN
Keyword(s):  
Cancer Treatment ◽  
Cell Lines ◽  
Prostatic Cancer ◽  
Nuclear Translocation ◽  
Metabolic Reprogramming ◽  
Dependent Manner ◽  
Cell Bank ◽  
Slc Transporters ◽  
Tumor Tissues

Abstract Background: Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood.Materials and methods: Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6~8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments.Result: Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2，3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment. Conclusion：Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.

The Antimalarial Agent Artesunate Overcomes Bortezomib Resistance in Myeloma Cell Lines Through Non-Caspase Mediated Apoptosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4015-4015
Author(s):  
Xenofon Papanikolaou ◽  
Ruslana Tytarenko ◽  
Tarun K. Garg ◽  
Sarah K. Johnson ◽  
Erming Tian ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Lines ◽  
Mode Of Action ◽  
Nuclear Translocation ◽  
Proteasome Inhibition ◽  
Cross Resistance ◽  
Dependent Manner ◽  
Caspase Activation ◽  
Rpmi 8226

Abstract Abstract 4015 During terminal differentiation of a B-lymphocyte to a mature plasma cell, the protein load increases considerably while the proteasome capacity decreases. The fact that plasma cells operate close to the limit of their proteasomal capacity is being exploited therapeutically and proteasome inhibition has become one of the pillars of myeloma treatment. The importance of the proteasome in Multiple Myeloma (MM) has also been established in prognostic terms (1). De novo or acquired resistance to proteasome inhibitors (PI) confers poor prognosis in MM. In vitro bortezomib resistance is accompanied by cross-resistance to other known PIs, thus highlighting (2), the need for treatment alternatives. Based on reports that various antimalarial drugs exhibit in vitro anti-MM activity through either α-ring proteasome inhibition (mefloquine) or aggresome formation inhibition (quinine), we examined whether Artesunate (ART), a new highly effective antimalarial drug with a known excellent safety profile, could overcome resistance to PI's currently in clinical use. Bortezomib (BZ)-resistant sublines of the BZ naïve and sensitive JJN3 and U266 cell lines were developed by exposure to progressively increasing BZ concentrations. Eventually the JJN3BR and U266BR sublines were developed with a 20- and 25-fold IC50 increase, respectively, compared to their BZ naïve counterparts. ART was able to inhibit viability in clinically achievable dosages and in a time-dependent manner in IL-6-independent and -dependent MM cell lines (Table 1). JJN3BR and U266BR showed no evidence of cross-resistance compared to their parental cell lines. The RPMI 8226 cell line known to exhibit one of the highest BZ IC50s among MM cell lines proved to be among the most sensitive to ART. The in-vitro antiMM effectiveness of ART was evident also in primary CD-138+ MM cells from six (6) patients with Relapsed/Refractory MM (Table 2). ART in-vitro anti MM activity was also verified by Annexin-V and 7-AAD flow cytometry for its ability to induce both early and late apoptosis. To elucidate ART's mode of action, we measured the sequence and level of caspase activation through the luminescence assay Caspase-Glo. ART exposure initiated the extrinsinc pathway of apoptosis with a brisk increase in activated caspase-8 levels and effector caspase3/7 levels within 3h, followed by caspase 9 activation at 6h. However, actual apoptosis by ART was not accompanied by a marked caspase activity especially when compared to other potent anti-MM agents. The pan-caspase inhibitor Z-VAD-MFK effectively inhibited caspase activation by ART but failed to inhibit ART's effect on viability, as at least 70% of ART's effect was retained in JJN3, U266 and RPMI 8226 cells. Similar results were obtained in flow cytometry-based apoptosis assays. Immunoblotting of the mitochondrial derived non-caspase mediating apoptosis factors AIF, EndoG and HtrA2 in ART treated JJN3 cells revealed that ART-mediated apoptosis was related to the cytoplasmic and subsequently nuclear translocation of AIF. Conclusion: ART shows marked anti-MM activity and overcomes BZ resistance in vitro. Its benign side effect profile support its potential for myeloma therapy. Most anti-cancer agents induce apoptosis in a caspase-dependent manner. ART's mode of action is mainly caspase-independent, indicating that its role in overcoming drug resistance, could also extend to other anti-MM agents. Experiments aimed at further elucidating the mechanism of action of ART and the evaluation of drug combinations including ART are currently under way. Disclosures: Tian: University of Arkansas for Medical Sciences: Employment, under pending process, under pending process Patents & Royalties.

scholarly journals Delivery of melittin-loaded niosomes for breast cancer treatment: an in vitro and in vivo evaluation of anti-cancer effect

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Farnaz Dabbagh Moghaddam ◽  
Iman Akbarzadeh ◽  
Ehsan Marzbankia ◽  
Mahsa Farid ◽  
Leila khaledi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cell Lines ◽  
Encapsulation Efficiency ◽  
Inbred Mice ◽  
Breast Cancer Treatment ◽  
Anticancer Effect ◽  
Anti Cancer

Abstract Background Melittin, a peptide component of honey bee venom, is an appealing candidate for cancer therapy. In the current study, melittin, melittin-loaded niosome, and empty niosome had been optimized and the anticancer effect assessed in vitro on 4T1 and SKBR3 breast cell lines and in vivo on BALB/C inbred mice. "Thin-layer hydration method" was used for preparing the niosomes; different niosomal formulations of melittin were prepared and characterized in terms of morphology, size, polydispersity index, encapsulation efficiency, release kinetics, and stability. A niosome was formulated and loaded with melittin as a promising drug carrier system for chemotherapy of the breast cancer cells. Hemolysis, apoptosis, cell cytotoxicity, invasion and migration of selected concentrations of melittin, and melittin-loaded niosome were evaluated on 4T1 and SKBR3 cells using hemolytic activity assay, flow cytometry, MTT assay, soft agar colony assay, and wound healing assay. Real-time PCR was used to determine the gene expression. 40 BALB/c inbred mice were used; then, the histopathology, P53 immunohistochemical assay and estimate of renal and liver enzyme activity for all groups had been done. Results This study showed melittin-loaded niosome is an excellent substitute in breast cancer treatment due to enhanced targeting, encapsulation efficiency, PDI, and release rate and shows a high anticancer effect on cell lines. The melittin-loaded niosome affects the genes expression by studied cells were higher than other samples; down-regulates the expression of Bcl2, MMP2, and MMP9 genes while they up-regulate the expression of Bax, Caspase3 and Caspase9 genes. They have also enhanced the apoptosis rate and inhibited cell migration, invasion in both cell lines compared to the melittin samples. Results of histopathology showed reduce mitosis index, invasion and pleomorphism in melittin-loaded niosome. Renal and hepatic biomarker activity did not significantly differ in melittin-loaded niosome and melittin compared to healthy control. In immunohistochemistry, P53 expression did not show a significant change in all groups. Conclusions Our study successfully declares that melittin-loaded niosome had more anti-cancer effects than free melittin. This project has demonstrated that niosomes are suitable vesicle carriers for melittin, compare to the free form.

scholarly journals The Modulation of PCSK9 and LDLR by Supercritical CO2 Extracts of Mentha longifolia and Isolated Piperitone Oxide, an In Vitro Study

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3886
Author(s):  
Stefania Sut ◽  
Irene Ferrarese ◽  
Maria Giovanna Lupo ◽  
Nicola De Zordi ◽  
Elisa Tripicchio ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Lines ◽  
Hepatoma Cell ◽  
Density Lipoprotein ◽  
In Vitro Study ◽  
Volatile Constituent ◽  
Dependent Manner ◽  
Human Hepatoma Cell ◽  
Concentration Dependent Manner

In the present study the ability of supercritical carbon dioxide (SCO2) extracts of M. longifolia L. leaves to modulate low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression was evaluated in cultured human hepatoma cell lines Huh7 and HepG2. Two SCO2 extracts, one oil (ML-SCO2) and a semisolid (MW-SCO2), were subjected to detailed chemical characterization by mono- and bidimensional nuclear magnetic resonance (1D, 2D-NMR), gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography coupled with mass spectrometry (LC-MS). Chemical analysis revealed significant amounts of fatty acids, phytosterols and terpenoids. ML-SCO2 was able to induce LDLR expression at a dose of 60 µg/mL in HuH7 and HepG2 cell lines. Furthermore, ML-SCO2 reduced PCSK9 secretion in a concentration-dependent manner in both cell lines. Piperitone oxide, the most abundant compound of the volatile constituent of ML-SCO2 (27% w/w), was isolated and tested for the same targets, showing a very effective reduction of PCSK9 expression. The overall results revealed the opportunity to obtain a new nutraceutical ingredient with a high amount of phytosterols and terpenoids using the SCO2 extraction of M. longifolia L., a very well-known botanical species used as food. Furthermore, for the first time we report the high activity of piperitone oxide in the reduction of PCSK9 expression.

scholarly journals Phaseolin Attenuates Lipopolysaccharide-Induced Inflammation in RAW 264.7 Cells and Zebrafish

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 420
Author(s):  
Su-Jung Hwang ◽  
Ye-Seul Song ◽  
Hyo-Jong Lee
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Raw 264.7 Cells ◽  
Network Pharmacology ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Bioactive Constituents

Kushen (Radix Sophorae flavescentis) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of S. flavescentis. However, the role of phaseolin (one of the primary components of S. flavescentis) in the direct regulation of inflammation and inflammatory processes is not well known. In this study, the beneficial role of phaseolin against inflammation was explored in lipopolysaccharide (LPS)-induced inflammation models of RAW 264.7 macrophages and zebrafish larvae. Phaseolin inhibited LPS-mediated production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), without affecting cell viability. In addition, phaseolin suppressed pro-inflammatory mediators such as cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in a dose-dependent manner. Furthermore, phaseolin reduced matrix metalloproteinase (MMP) activity as well as macrophage adhesion in vitro and the recruitment of leukocytes in vivo by downregulating Ninjurin 1 (Ninj1), an adhesion molecule. Finally, phaseolin inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB). In view of the above, our results suggest that phaseolin could be a potential therapeutic candidate for the management of inflammation.

scholarly journals Human Proximal Tubule Epithelial Cells (HK-2) as a Sensitive In Vitro System for Ochratoxin A Induced Oxidative Stress

Toxins ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 787
Author(s):  
Enrique García-Pérez ◽  
Dojin Ryu ◽  
Hwa-Young Kim ◽  
Hae Dun Kim ◽  
Hyun Jung Lee
Keyword(s):  
Oxidative Stress ◽  
Ochratoxin A ◽  
Cell Lines ◽  
Time Dependent ◽  
Mrna Levels ◽  
Dependent Manner ◽  
In Vitro System ◽  
Glutathione Peroxidase 1 ◽  
Glucose 6 Phosphate Dehydrogenase

Ochratoxin A (OTA) is a mycotoxin that is potentially carcinogenic to humans. Although its mechanism remains unclear, oxidative stress has been recognized as a plausible cause for the potent renal carcinogenicity observed in experimental animals. The effect of OTA on oxidative stress parameters in two cell lines of LLC-PK1 and HK-2 derived from the kidneys of pig and human, respectively, were investigated and compared. We found that the cytotoxicity of OTA on LLC-PK1 and HK-2 cells was dose- and time-dependent in both cell lines. Furthermore, increased intracellular reactive oxygen species (ROS) induced by OTA in both cell lines were observed in a time-dependent manner. Glutathione (GSH) was depleted by OTA at >48 h in HK-2 but not in LLC-PK1 cells. While the mRNA levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione peroxidase 1 (GPX1) in LLC-PK1 were down-regulated by 0.67- and 0.66-fold, respectively, those of catalase (CAT), glutathione reductase (GSR), and superoxide dismutase 1 (SOD) in HK-2 were up-regulated by 2.20-, 2.24-, and 2.75-fold, respectively, after 72 h exposure to OTA. Based on these results, we conclude that HK-2 cells are more sensitive to OTA-mediated toxicity than LLC-PK1, and OTA can cause a significant oxidative stress in HK-2 as indicated by changes in the parameter evaluated.

scholarly journals In vitro cytotoxic study for partially purified resveratrol extracted from grape skin fruit Vitis vinifera

2009 ◽  
Vol 3 (2) ◽  
pp. 40-47
Author(s):  
Zainab Y. Mohammed ◽  
Essam F. Al-Jumaily ◽  
Nahi Y. Yaseen
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Inhibitory Effect ◽  
Mammary Adenocarcinoma ◽  
Dependent Manner ◽  
Grape Skin ◽  
Grape Fruit ◽  
Glass Column

The partial purified resveratrol was obtained from the skin of black grape fruit cultivated in Iraq using 80% ethanolic solution, then an acid hydrolysis with 10% HCl solution for (10–30) min at 60Cº was carried out. The aglycone moiety was taken with an organic solvent (chloroform), then using an open glass column packed with silica gelG 60 as a stationary phase and a mobile phase of; benzene: methanol: actic acid (20:4:1). The study utilized an in vitro evaluation for the cytotoxic effect of the partially purified resveratrol on some cell lines including, the murine mammary adenocarcinoma (Ahmed –Mohammed –Nahi–2003 -AMN -3) cell line; the human laryngeal carcinoma (Hep -2) cell line and the Rat Embryo Fibroblast (REF) cell line at different concentrations and different exposure time of treatment. The partial purified resveratrol extract concentrations ranging (7.8–4000) µg/ml in a two fold serial dilutions were used to treat the three types of cell lines for 48 and 72 hours intervals. AMN-3 cell lines showed highest sensitivity toward the cytotoxic effect of the paritial purified resveratrol than other cell lines after 48 hours in a dose dependent manner. While Hep-2 cell line showed novel behavior, the lowest concentration of cell treatment gave the most significant (P< 0.01) inhibitory effect. Only the highest concentration gave significant inhibitory effect (P< 0.01) with the transformed Ref cell line.

scholarly journals PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Qingmin Sun ◽  
Mengyun Yuan ◽  
Hongxing Wang ◽  
Xingxing Zhang ◽  
Ruijuan Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients.Chemical Compounds Studied in this ArticleRutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).

Synthesis and Biological Evaluation of Novel 4-Phenylaminobenzofuro[2,3-d]pyrimidine Derivatives

2020 ◽  
Vol 42 (4) ◽  
pp. 564-564
Author(s):  
Ju liu Ju liu ◽  
Jun Li Jun Li ◽  
Jian tao Shi Jian tao Shi ◽  
Jie Li Jie Li ◽  
Xue chen Hao Xue chen Hao ◽  
...  
Keyword(s):  
Cell Lines ◽  
A549 Cells ◽  
Positive Control ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Pyrimidine Derivatives ◽  
Concentration Dependent Manner ◽  
Ic50 Value ◽  
Synthesis And Biological Evaluation

A series of novel 4-phenylaminobenzofuro[2,3-d]pyrimidine derivatives had been prepared and assessed for their in vitro antiproliferative activities against three lung cancer cell lines (A549, H460 and H1975). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activities. Among them, compound 8f exhibited remarkable inhibitory activity against A549 and H460 cell lines with IC50 value of 2.54 μM and 2.68 μM, respectively, which was comparable to that of the positive control sorafenib (IC50 = 2.69 μM for A549 and 3.71 μM for H460). AO/EB staining suggests that compound 8f could induce apoptosis in A549 cells. Furthermore, cell cycle analyses show that compound 8f increased G0/G1 A549 cells arrest in a concentration-dependent manner. The preliminary structure-activity relationships (SARs) studies indicated that mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring are positive on the antitumor activity.

scholarly journals Design, Synthesis and Biological Evaluation of a New Series of 1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea Derivatives as Antiproliferative Agents

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2108 ◽  
Author(s):  
Chuanming Zhang ◽  
Xiaoyu Tan ◽  
Jian Feng ◽  
Ning Ding ◽  
Yongpeng Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
A549 Cells ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Urea Derivatives ◽  
Antiproliferative Agents

To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the target compounds demonstrated significant antiproliferative effects on all the selective cancer cell lines. Among them, the target compound, 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}urea (7i) was identified to be the most active one against three cell lines, which was more potent than the positive control with an IC50 value of 1.53 ± 0.46, 1.11 ± 0.34 and 1.98 ± 1.27 μM, respectively. Further cellular mechanism studies confirmed that compound 7i could induce the apoptosis of A549 cells in a concentration-dependent manner and elucidated compound 7i arrests cell cycle at G1 phase by flow cytometry analysis. Herein, the studies suggested that the 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea skeleton might be regarded as new chemotypes for designing effective antiproliferative agents.

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