scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

2016 ◽  
Vol 291 (33) ◽  
pp. 17405-17416 ◽  
Author(s):  
Yang Zhang ◽  
Yi Zhang ◽  
Liying Geng ◽  
Haowei Yi ◽  
Wei Huo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Mouse Xenograft Model

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

Effect of AbGn-7, a glycotope-specific monoclonal antibody, on apoptosis in colon cancer cells and tumor growth in xenograft models

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15118-e15118
Author(s):  
S. Lin ◽  
E. Chiang ◽  
Y. Tsai ◽  
S. Lee ◽  
B. Kuo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Colon Cancer ◽  
Monoclonal Antibodies ◽  
Cancer Cells ◽  
Parp Cleavage ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Dose Dependent

e15118 Background: While clinical benefit against colorectal cancer has been observed with therapeutic monoclonal antibodies such as bevacizumab, cetuximab and panituzumab, the death rate of advanced colorectal cancer remains high that warrants further development of more potent therapeutics. Methods: A cell-based immunization approach was used to generate monoclonal antibodies against targets expressed on human colorectal cancer cells. A chimeric monoclonal antibody, AbGn-7, was selected and evaluated for the potential clinical use to treat colorectal cancer. Results: Expression of AbGn-7 antigen: Carbohydrate competition assay demonstrated that AbGn-7 recognizes a Lewis-A-like carbohydrate antigen (AbGn-7 antigen). Immunohistochemical studies showed that AbGn-7 antigen is expressed in colorectal cancer tissue. No significant binding could be detected in non-tumor tissues except in the epithelia of GI track. Effector function of AbGn-7: AbGn-7 triggered dose-dependent apoptosis in COLO 205 colon cancer cell. In addition, AbGn-7 elicited potent complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in a dose-dependent manner. Molecular mechanism of apoptosis induced by AbGn-7: Tunel assay, PARP cleavage assay as well as caspase inhibitor studies demonstrated that AbGn-7 induced apoptosis in COLO 205 colon cancer cells via a caspase-independent pathway. Xenograft study: AbGn-7 alone, or in combination with 5FU-Leucovorin, effectively inhibited the growth of COLO 205 xenograft in SCID mice and prolonged their survival. Conclusions: The results of the present study suggest that AbGn-7 is a potential candidate for effective treatment of colorectal cancer. [Table: see text]

Verbascoside Attenuates Rac-1 and HIF-1α Signaling Cascade in Colorectal Cancer Cells

2019 ◽  
Vol 18 (15) ◽  
pp. 2149-2155
Author(s):  
Danial Seyfi ◽  
Seyed B. Behzad ◽  
Mohammad Nabiuni ◽  
Kazem Parivar ◽  
Mohammad Tahmaseb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Real Time ◽  
Real Time Pcr ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Ht29 Cells ◽  
Colorectal Cancer Cells

Objective: Metastasis phenotype is considered as the main challenge in colon cancer therapeutic methods. Furthermore, the side effects of conventional colorectal cancer treatment methods have attracted a lot of attention into natural ingredients. The aim of the study was to assess the molecular mechanism of verbascoside as natural bio-compound in human HT29 colon cancer cells. Methods: HT29 cells were cultured in RPMI-1640 medium containing 10% FBS and 1% penicillin/ streptomycin at 37°C and 5% CO2. HT-29 cells were treated with different concentrations of verbascoside (10, 20, 30, 40, 50, 70, 100 µg/ml) for 24 hours, then MTT assay was used to calculate 50% inhibitory concentration. The migration of the colon cancer cells was evaluated by scratch assay. To evaluate involved antiproliferative mechanism, Rac-1 (Ras-related C3 botulinum toxin substrate 1) and HIF-1α (hypoxia-inducible factor-1α) related gene expression were evaluated by Real Time PCR. Results: The results showed that verbascoside inhibited HT29 colon cancer cell proliferation dose-dependently and IC50 was evaluated as 50 μg/ml (***P<0.001). The results of wound healing assay demonstrated verbascoside decreased cell migration in a dose dependent manner. In the IC50 treated HT29 cells metastatic progression was significantly suppressed as **P<0.01. The results of Real Time PCR showed an attenuating effect of verbascoside on Rac-1, Zeb-1 (zinc finger E-box binding homeobox 1), Arp2 (Actin-Related Proteins), Pak1 (p21 (RAC1) activated kinase 1), VEGF (Vascular endothelial growth factor) and HIF-1α as Epithelial-Mesenchymal Transition markers. The down regulation of mRNA levels was Rac-1= 15.38, HIF-1 α = 16.66, Pak-1, Arp-2= 6.25, VEGF=24.39, Zeb-1=35.71 in HT29 cells treated with IC50 concentration of verbascoside. Conclusion: Colorectal cancer cells induce Rac-1 and HIF-1α overexpression which plays an important role in the activation and progression of cell motility, angiogenesis and metastasis. Overall results showed that verbascoside elucidated significant anti-metastatic and anti-invasion activities through suppression of Rac-1, HIF-1α, and Zeb-1 signaling pathway and it may be a suitable candidate to overwhelm colon cancer metastatic phenotype.

scholarly journals Autophagy Induction by Trichodermic Acid Attenuates Endoplasmic Reticulum Stress-Mediated Apoptosis in Colon Cancer Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5566
Author(s):  
Junyan Qu ◽  
Cheng Zeng ◽  
Tingting Zou ◽  
Xu Chen ◽  
Xiaolong Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Cancer Cells ◽  
Protective Mechanism ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Antitumor Effects

Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.

scholarly journals Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation

2018 ◽  
Vol 115 (29) ◽  
pp. E6760-E6769 ◽  
Author(s):  
Jiuli Zhou ◽  
Yongji Zeng ◽  
Lian Cui ◽  
Xingcheng Chen ◽  
Seth Stauffer ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Critical Role ◽  
Ectopic Expression ◽  
Tumor Formation ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Mitotic Phosphorylation

Zyxin is a member of the focal adhesion complex and plays a critical role in actin filament polymerization and cell motility. Several recent studies showed that Zyxin is a positive regulator of Yki/YAP (Yes-associated protein) signaling. However, little is known about the mechanisms by which Zyxin itself is regulated and how Zyxin affects Hippo–YAP activity. We first showed that Zyxin is phosphorylated by CDK1 during mitosis. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, anchorage-independent growth, and tumor formation in xenograft animal models. Mitotic phosphorylation is required for Zyxin activity in promoting growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. CDK8 knockout phenocopied Zyxin knockdown in colon cancer cells, while ectopic expression of CDK8 substantially restored the tumorigenic defects of Zyxin-depletion cells. Mechanistically, we showed that CDK8 directly phosphorylated YAP and promoted its activation. Fully activated YAP is required to support the growth in CDK8-knockout colon cancer cells in vitro and in vivo. Together, these observations suggest that Zyxin promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP activation.

Serine/Arginine Repetitive Matrix 2 Antisense RNA 1 Negatively Regulates miR-370-3p and Promotes Hyperplasia, Migration, and Aggression of the Colon Cancer Cell Line

2021 ◽  
Vol 11 (6) ◽  
pp. 1059-1065
Author(s):  
Lixin Zhu ◽  
Qinx Wang ◽  
Chen Yang
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Healing Rate ◽  
Colon Cancer Cells ◽  
Protein Levels ◽  
Sw1116 Cell ◽  
E Cadherin

The purpose of this study is to explore the effect and possible machine-processing of the long non-coding RNA (lncRNA) SRRM2-AS1 in the development and pathogenesis of colorectal cancer. LncRNA plays an important role in tumorigenesis and development. LncRNA can regulate gene transcription and translation, cell proliferation, differentiation and apoptosis by affecting gene expression pathways of various coding proteins. SRRM2-AS1 is a kind of lncRNA. Studies have confirmed that the expression of SRRM2-AS1 is increased in colon adenocarcinoma tissues of colon cancer patients and is closely related to the prognosis of patients. However, the influence and molecular mechanism of SRRM2-AS1 on the malignant biological behavior of colon cancer cells are no yet clear. SRRM2-AS1 may interact with miR-370-3p. Studies have confirmed that overexpression of miR-370-3p can inhibit the proliferation and epithelial-mesenchymal transition of colon cancer cells in vitro. However, it is not yet clear whether SRRM2-AS1 can target miR-370-3p to affect the occurrence and development of tumors. In this study, RT-qPCR was employed to detect levels of SRRM2-AS1 and miRNA-370-3p in carcinoma tissues and corresponding paracarcinoma tissues from 41 patients with colon cancer. SW1116 colon cancer cells were cultured in vitro and separated into 4 groups: (1) si-NC group, (2) si-SRRM2-AS1 group, (3) si-SRRM2-AS1+anti-miRNA-NC group, and (4) si-SRRM2-AS1+anti-miRNA-370-3p group. The CCK-8 assay and colony formation experiment was employed to gauge cell proliferation. The scratch test was used to detect cell migration while the transwell assay was used to detect cell invasion. Finally, Western blot analysis was employed to detect levels of Ki67, E-cadherin, and N-cadherin proteins in colorectal cancer cells. The dual-luciferase reporter gene experiment verified that SRRM2-AS1 regulates miRNA-370-3p. The study found that compared to paracarcinoma tissue, levels of SRRM2-AS1 in colon cancer tissues was increased (P < 0.05). Compared to the si-NC group, the SW1116 cell OD value, number of colonies formed, scratch healing rate, number of invasive cells, and expression levels of Ki67 and N-cadherin protein in the si-SRRM2-AS1 group were all decreased (P < 0.05). However, E-cadherin protein levels were elevated (P < 0.05). SRRM2-AS1 negatively regulates levels of miRNA-370-3p in SW1116 cells. Compared to the si-SRRM2-AS1+anti-miRNA-NC group, SW1116 cell OD value, number of colonies formed, scratch healing rate, number of invasive cells, and Ki67 and N-cadherin protein levels were increased (P < 0.05) in the si-SRRM2-AS1+anti-miRNA-370-3p group. Conversely, E-cadherin protein levels were decreased (P < 0.05). These findings indicate that SRRM2-AS1 is predominately expressed in cancerous colon tissues. Attenuating expression of SRRM2-AS1 may curb the hyperplasia of colon carcinoma cell line SW1116 and promote cell apoptosis by regulating miRNA-370-3p expression.

scholarly journals Effect of rs67085638 in long non-coding RNA (CCAT1) on colon cancer chemoresistance to paclitaxel through modulating the microRNA-24-3p and FSCN1 signaling

2020 ◽  
Author(s):  
Caihong Zhang ◽  
Yonglin Wang
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Luciferase Assay ◽  
Pcr Analysis ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels ◽  
The Difference

Abstract BackgroundIt has been reported that rs67085638 in lncRNA-CCAT1 was associated with the risk of tumorigenesis. Also, CCAT1 could affect chemoresistance of cancer cells to PTX via regulating miR-24-3p and FSCN1 expression. In this study, we aimed to investigate the effect of rs67085638 on the expression of CCAT1/miR-24-3p/FSCN1 and the response of colon cancer to the treatment of PTX.Method48 colon cancer patients were recruited and grouped by their genotypes of rs67085638 polymorphism as a CC group (N=28) and a CT group (N=20). Colon cancer cells were collected from the patients and cancer cell xenografts were transplanted into mice. PCR analysis, IHC assay and Western blot were performed to observe the expression of lncRNA-CCAT1, miR-24-3p and FSCN1 in vivo and in vitro, and the relationships among the expression of lncRNA-CCAT1, miR-24-3p and FSCN1 were validated by computational analysis and luciferase assay. TUNEL assay and flow cytometry were conducted to observe tumor cell apoptosis and survival.ResultLncRNA-CCAT1 and FSCN1 mRNA/protein were over-expressed while miR-24-3p was down-regulated in the CT-genotyped patients and cells compared with those in the CC-genotyped patients and cells. The survival of colon cancer cells was decreased while the apoptosis of colon cancer cells was increased by PTX treatment in a dose-dependent manner. However, the survival rate of CT-genotyped cells was higher while the apoptosis rate of CT-genotyped cells was lower than that of the CC-genotyped cells, and the difference was partly eliminated by the knockdown of lncRNA-CCAT1. MiR-24-3p was validated to target lncRNA-CCAT1 and FSCN1 mRNA, and the over-expression of CCAT1 could reduce the expression of miR-24-3p while elevating the expression of FSCN1. The growth of CT-genotyped tumors in mice was more suppressed in compared with the growth of CC-genotyped tumors, while the knockdown of lncRNA-CCAT1 partly reversed the effect of the CT genotype. Furthermore, compared with the rs67085638-CC mice, the lncRNA-CCAT1 and FSCN1 mRNA/protein levels in the rs67085638-CT+NC shRNA mice were increased while their miR-24-3p level was decreased, and the knockdown of lncRNA-CCAT1 partly reversed the dysregulation of these genes.ConclusionThe findings of this study demonstrated that the presence of the minor allele of rs67085638 increased the expression of CCAT1 and accordingly enhanced the resistance to PTX. Downregulation of CCAT1 partially, but significantly, re-stored the sensitivity to PTX of colon cancer cells.

scholarly journals Cytotoxicity and Apoptosis Effects of Curcumin Analogue (2E,6E)-2,6-Bis(2,3-Dimethoxybenzylidine) Cyclohexanone (DMCH) on Human Colon Cancer Cells HT29 and SW620 In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1261
Author(s):  
Nurul Fattin Che Rahim ◽  
Yazmin Hussin ◽  
Muhammad Nazirul Mubin Aziz ◽  
Nurul Elyani Mohamad ◽  
Swee Keong Yeap ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Curcuma Longa ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Sw620 Cell

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012–2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.

scholarly journals Integrated analysis of potential pathways by which aloe-emodin induces the apoptosis of colon cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dongxiao Jiang ◽  
Shufei Ding ◽  
Zhujun Mao ◽  
Liyan You ◽  
Yeping Ruan
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Time Dependent ◽  
Integrated Analysis ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Dapi Staining ◽  
Aloe Emodin

Abstract Background Colon cancer is a malignant gastrointestinal tumour with high incidence, mortality and metastasis rates worldwide. Aloe-emodin is a monomer compound derived from hydroxyanthraquinone. Aloe-emodin produces a wide range of antitumour effects and is produced by rhubarb, aloe and other herbs. However, the mechanism by which aloe-emodin influences colon cancer is still unclear. We hope these findings will lead to the development of a new therapeutic strategy for the treatment of colon cancer in the clinic. Methods We identified the overlapping targets of aloe-emodin and colon cancer and performed protein–protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. In addition, we selected apoptosis pathways for experimental verification with cell viability, cell proliferation, caspase-3 activity, DAPI staining, cell cycle and western blotting analyses to evaluate the apoptotic effect of aloe-emodin on colon cancer cells. Results The MTT assay and cell colony formation assay showed that aloe-emodin inhibited cell proliferation. DAPI staining confirmed that aloe-emodin induced apoptosis. Aloe-emodin upregulated the protein level of Bax and decreased the expression of Bcl-2, which activates caspase-3 and caspase-9. Furthermore, the protein expression level of cytochrome C increased in a time-dependent manner in the cytoplasm but decreased in a time-dependent manner in the mitochondria. Conclusion These results indicate that aloe-emodin may induce the apoptosis of human colon cancer cells through mitochondria-related pathways.

scholarly journals Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4417
Author(s):  
Rabin Neupane ◽  
Saloni Malla ◽  
Mariam Sami Abou-Dahech ◽  
Swapnaa Balaji ◽  
Shikha Kumari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Colon Cancer Cells ◽  
Apoptotic Pathway ◽  
Anticancer Efficacy ◽  
Colon Cell ◽  
Ic50 Values ◽  
Induced Apoptosis

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

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