Atractylenolide III induces apoptosis by regulating the Bax/Bcl-2 signaling pathway in human colorectal cancer HCT-116 Cells in vitro and in vivo

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Dan Zhang ◽  
Xiaofang Xiao ◽  
Daqiang Song ◽  
Siwei Chen ◽  
Zhuo Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Human Colorectal Cancer ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Atractylenolide Iii

scholarly journals Photodynamic therapy induces autophagy-mediated cell death in human colorectal cancer cells via activation of the ROS/JNK signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Changfeng Song ◽  
Wen Xu ◽  
Hongkun Wu ◽  
Xiaotong Wang ◽  
Qianyi Gong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Photodynamic Therapy ◽  
Signaling Pathway ◽  
Tumor Promoter ◽  
Human Colorectal Cancer ◽  
In Vivo Models ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

Abstract Evidence has shown that m-THPC and verteporfin (VP) are promising sensitizers in photodynamic therapy (PDT). In addition, autophagy can act as a tumor suppressor or a tumor promoter depending on the photosensitizer (PS) and the cancer cell type. However, the role of autophagy in m-THPC- and VP-mediated PDT in in vitro and in vivo models of human colorectal cancer (CRC) has not been reported. In this study, m-THPC-PDT or VP-PDT exhibited significant phototoxicity, inhibited proliferation, and induced the generation of large amounts of reactive oxygen species (ROS) in CRC cells. From immunoblotting, fluorescence image analysis, and transmission electron microscopy, we found extensive autophagic activation induced by ROS in cells. In addition, m-THPC-PDT or VP-PDT treatment significantly induced apoptosis in CRC cells. Interestingly, the inhibition of m-THPC-PDT-induced autophagy by knockdown of ATG5 or ATG7 substantially inhibited the apoptosis of CRC cells. Moreover, m-THPC-PDT treatment inhibited tumorigenesis of subcutaneous HCT116 xenografts. Meanwhile, antioxidant treatment markedly inhibited autophagy and apoptosis induced by PDT in CRC cells by inactivating JNK signaling. In conclusion, inhibition of autophagy can remarkably alleviate PDT-mediated anticancer efficiency in CRC cells via inactivation of the ROS/JNK signaling pathway. Our study provides evidence for the therapeutic application of m-THPC and VP in CRC.

scholarly journals Effective Sequential Combined Chemotherapy with Trifluridine/Tipiracil and Regorafenib in Human Colorectal Cancer Cells

2018 ◽  
Vol 19 (10) ◽  
pp. 2915 ◽  
Author(s):  
Kazuaki Matsuoka ◽  
Fumio Nakagawa ◽  
Nozomu Tanaka ◽  
Hiroyuki Okabe ◽  
Kenichi Matsuo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Sequential Therapy ◽  
Salvage Chemotherapy ◽  
Human Colorectal Cancer ◽  
Antitumor Effects ◽  
Hct 116 ◽  
Ht 29

Salvage chemotherapy for refractory metastatic colorectal cancer using trifluridine/tipiracil (FTD/TPI) and regorafenib has shown survival benefits. We evaluated the antitumor effects of FTD or FTD/TPI combined with regorafenib in vitro and in vivo. SW620, HCT 116, and HT-29 human colorectal cancer cell lines were treated with FTD and regorafenib simultaneously and sequentially. Cell death, incorporation of FTD into DNA, and molecules related to FTD and regorafenib-associated cell death were investigated. The antitumor effects of FTD combined with regorafenib in SW620 and COLO205 xenografts were also evaluated. Cell death was greater after sequential treatment with FTD followed by regorafenib in SW620 cells, but not in HCT 116 and HT-29 cells, than after treatment with FTD alone, which was attributable to thymidylate synthase reduction with the induction of apoptosis. In contrast, simultaneous and sequential exposure to regorafenib followed by FTD, but not FTD alone, attenuated the cell death effect. Furthermore, combined FTD/TPI treatment followed by regorafenib had greater antitumor activity than either monotherapy in SW620 and COLO205 xenograft models. Treatment results following regorafenib administration subsequent to FTD or FTD/TPI suggest that sequential therapy with FTD/TPI prior to regorafenib may be effective in a clinical setting.

scholarly journals Isoliquiritigenin inhibits colorectal cancer cells HCT-116 growth by suppressing the PI3K/AKT pathway

2017 ◽  
Vol 12 (1) ◽  
pp. 300-307 ◽  
Author(s):  
Ya-Li Huang ◽  
Fang Wei ◽  
Ke Zhao ◽  
Yong Zhang ◽  
Dong Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Human Colorectal Cancer ◽  
Sds Page ◽  
Colorectal Cancer Cells ◽  
Hct 116 ◽  
Hct 116 Cells

AbstractIsoliquiritigenin (ISL), a member of the flavonoids, is known to possess antitumor activity in different types of cancer including human breast cancer, hepatoma cancer, prostate cancer and others, bothin vitroandin vivo. In the present study, we reported the effect of ISL on cell growth in human colorectal cancer cells HCT-116. As examined by CCK8 assays, ISL inhibited the proliferation of HCT-116 cells. Additionally, the antimigratory activity of ISL in HCT-116 cells was confirmed by trans-well chamber migration assays and invasion assays. Moreover, the results of fluorescence-activated cell sorting and Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) analysis showed that ISL induced apoptosis in HCT-116 cells. Further detection using SDS-PAGE assay revealed that ISL decreased the levels of phospho-AKT (p-AKT), phospho-mTOR (p-mTOR), Cyclin D1 and phospho-p70S6 Kinase (p-P70S6K). Collectively, these findings indicated that isoliquiritigenin induced growth-inhibition and apoptosis through downregulating of PI3K/AKT in human colorectal cancer.

Bioactive Peptides Sensitize Cells to Anticancer Effects of Oxaliplatin in Human Colorectal Cancer Xenografts in Nude Mice

2019 ◽  
Vol 26 (7) ◽  
pp. 512-522
Author(s):  
Xian Li ◽  
Long Xia ◽  
Xiaohui Ouyang ◽  
Qimuge Suyila ◽  
Liya Su ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Nude Mice ◽  
Low Dose ◽  
Bioactive Peptides ◽  
Human Colorectal Cancer ◽  
Short Term ◽  
Hct 116

<P>Background: Despite new agent development and short-term benefits in patients with Colorectal Cancer (CRC), metastatic CRC cure rates have not improved due to high rates of oxaliplatin resistance and toxicity. There is an urgent need for effective tools to prevent and treat CRC and reduce morbidity and mortality of CRC patients. Exploring the effects of bioactive peptides on the antitumor to CRC was of vital importance to the clinical application. </P><P> Objective: This study aimed to investigate the therapeutic impact of Anticancer Bioactive Peptides (ACBP) on anticancer effect of oxaliplatin (LOHP) in human colorectal cancer xenografts models in nude mice. </P><P> Methods: HCT-116 cells were cultured in vitro via CCK-8 assays and the absorbance was measured at 450 nm. Apoptosis and cell cycle were assessed by Flow Cytometry (FCM) in vitro. HCT-116 human colorectal cancer cells inoculated subcutaneously in nude mice of treatment with PBS (GG), ACBP, LOHP, ACBP+LOHP (A+L) in vivo. The quality of life was assessed by dietary amount of nude mice, the weight of nude mice, inhibition rates, tumor weight and tumor volume. Immunohistochemistry and RT-qPCR method was conducted to determine the levels of apoptosisregulating proteins/genes in transplanted tumors. </P><P> Results: ACBP induced substantial reductions in viable cell numbers and apoptosis of HCT116 cells in combined with LOHP in vitro. Compared with the control GG group, ACBP combined low dose oxaliplatin (U) group demonstrated significantly different tumor volume, the rate of apoptosis, the expression levels of Cyt-C, caspase-3,8,9 proteins and corresponding RNAs (P<0.05). The expression of pro-apoptotic proteins in the cytoplasm around the nucleus was significantly enhanced by ACBP. Short term intermittent use of ACBP alone indicted a certain inhibitory effect on tumor growth, and improve the quality of life of tumor bearing nude mice. </P><P> Conclusion: ACBP significantly increased the anti-cancer responses of low dose oxaliplatin (L-LOHP), thus, significantly improving the quality of life of tumor-bearing nude mice.</P>

Photodynamic Treatment of Colorectal Cancer Using Chlorin e6-Loaded Poly(lactide-co-glycolide)- Based Nanoparticles

2021 ◽  
Vol 17 (10) ◽  
pp. 1939-1950
Author(s):  
Beibei Lin ◽  
Xuegu Xu ◽  
Xiaobi Zhang ◽  
Yinfei Yu ◽  
Xiaoling Wang
Keyword(s):  
Colorectal Cancer ◽  
Drug Loading ◽  
Average Diameter ◽  
Plga Nanoparticles ◽  
Chlorin E6 ◽  
Photodynamic Treatment ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
The Stability

We prepared poly(lactide-co-glycolide) (PLGA) encapsulated with chlorin e6 (Ce6) in an effort to increase the stability and efficiency of photosensitizers for photodynamic therapy (PDT). We determined that Ce6-loaded PLGA nanoparticles (PLGA-Ce6 NPs) had drug-loading efficiency of 5%. The efficiency of encapsulation was 82%, the zeta potential was- 25 mV, and the average diameter was 130 nm. The encapsulation of Ce6 in PLGA nanoparticles showed excellent stability. The nanoparticles exhibited sustained Ce6 release profiles with 50% released at the end of 3 days, whereas free Ce6 showed rapid release within 1 day. Ce6 release patterns were controlled by encapsulation into PLGA. The uptake of PLGA-Ce6 NPs was significantly enhanced by endocytosis in the first 8 hours in the HCT-116 cell line. An intracellular reactive oxygen species assay revealed the enhanced uptake of the nanoparticles. An in vitro anti-tumor activity assay showed that the PLGA-Ce6 NPs exhibited enhanced phototoxicity toward HCT-116 cells and a slightly lower IC50 value in HCT-116 cells than Ce6 solution alone. Exposure of HCT-116 cell spheroids to PLGA-Ce6 NPs penetrated more profoundly and had better phototoxicity than pure drugs. These findings suggest that PLGA-Ce6 NPs might serve as PDT for colorectal cancer.

scholarly journals Gambogic Acid Efficiently Kills Stem-Like Colorectal Cancer Cells by Upregulating ZFP36 Expression

2018 ◽  
Vol 46 (2) ◽  
pp. 829-846 ◽  
Author(s):  
Fang Wei ◽  
Tong Zhang ◽  
Zhi Yang ◽  
Jian-Chang Wei ◽  
Hong-Fen Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Signaling Pathway ◽  
Bioluminescence Imaging ◽  
Side Population ◽  
Gambogic Acid ◽  
Tumor Sphere ◽  
Sphere Formation

Background/Aims: Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported to be a potential novel antitumor drug. Whether GA inhibits putative cancer stem cells (CSCs), which are considered to be the major cause of cancer treatment failure, remains largely unknown. This study investigated whether GA inhibits the CSCs of colorectal cancer (CRC) and its possible mechanisms. Methods: We performed CCK8 and tumor sphere formation assays, percentage analysis of both side population and CD133+CD44+ cells, and the detection of stem cells markers, in order to assess the role of GA in inhibiting the stem celllike features of CRC. An mRNA microarray was performed to identify the downstream gene affected by GA and rescue assays were performed to further clarify whether the downstream gene is involved in the GA induced decrease of the stem cell-like CRC population. CRC cells were engineered with a CSC detector vector encoding GFP and luciferase (Luc) under the control of the Nanog promoter, which were utilized to investigate the effect of GA on putative CSC in human tumor xenograft-bearing mice using in vivo bioluminescence imaging. Results: Our results showed that GA significantly reduced tumor sphere formation and the percentages of side population and CD133+CD44+ cells, while also decreasing the expression of stemness and EMT-associated markers in CRC cells in vitro. GA killed stem-like CRC cells by upregulating the expression of ZFP36, which is dependent on the inactivation of the EGFR/ ERK signaling pathway. GFP+ cells harboring the PNanog-GFP-T2A-Luc transgene exhibited CSC characteristics. The in vivo results showed that GA significantly inhibited tumor growth in nude mice, accompanied by a remarkable reduction in the putative CSC number, based on whole-body bioluminescence imaging. Conclusion: These findings suggest that GA significantly inhibits putative CSCs of CRC both in vitro and in vivo by inhibiting the activation of the EGFR/ ERK/ZFP36 signaling pathway and may be an effective drug candidate for anticancer therapies.

CIP4 Targeted to Recruit GTP-Cdc42 Involving in Invadopodia Formation Through NF-κB Signaling Pathway Promotes Invasion and Metastasis of Colorectal Cancer

2021 ◽  
Author(s):  
Zhiyan Hu ◽  
Jiaxian Zhu ◽  
Yidan Ma ◽  
Ting Long ◽  
Lingfang Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Tumor Metastasis ◽  
Migration And Invasion ◽  
Downstream Signaling ◽  
And Function ◽  
Downstream Signaling Pathway ◽  
Invadopodia Formation

Abstract Background CIP4 (Cdc42-interacting protein 4), a member of the F-BAR family which plays an important role in regulating cell membrane and actin, has been reported to interact with Cdc42 and closely associated with tumor invadopodia formation. However, the specific mechanism of the interaction between CIP4 and Cdc42 as well as the downstream signaling pathway in response in colorectal cancer (CRC) remains unknown, which is worth exploring for its impact on tumor infiltration and metastasis. Methods Immunohistochemistry and western blot analyses were performed to detect the expression of CIP4 and Cdc42. Their relationship with CRC clinicopathological characteristics was further analyzed. Wound-healing, transwell migration and invasion assays tested the effect of CIP4 on cells migration and invasion ability in vitro, and the orthotopic xenograft colorectal cancer mouse mode evaluated the tumor metastasis in vivo. The invadopodia formation and function were assessed by immunofluorescence, scanning electron microscopy (SEM) and matrix degradation assay. The interaction between CIP4 and Cdc42 was confirmed by co-immunoprecipitation (co-IP) and GST-Pull down assays. Immunofluorescence was used to observed the colocalization of CIP4, GTP-Cdc42 and invadopodia. The related downstream signaling pathway was investigated by western blot and immunofluorescence. Results CIP4 expression was significantly higher in human colorectal cancer tissues and correlated with the CRC infiltrating depth and metastasis as well as the lower survival rate in patients. In cultured CRC cells, knockdown of CIP4 inhibited cell migration and invasion ability in vitro and the tumor metastasis in vivo, while overexpression of CIP4 confirmed the opposite situation by promoting invadopodia formation and matrix degradation ability. In addition, we identified GTP-Cdc42 as a directly interactive protein of CIP4, which was upregulated and recruited by CIP4 to participate in this process. Furthermore, activated NF-κB signaling pathway was found in CIP4 overexpression CRC cells contributing to invadopodia formation while inhibition of either CIP4 or Cdc42 led to suppression of NF-κB pathway resulted in decrease quantity of invadopodia. Conclusion Our findings suggested that CIP4 targets to recruit GTP-Cdc42 and directly combines with it to accelerate invadopodia formation and function by activating NF-κB signaling pathway, thus promoting CRC infiltration and metastasis.

Tanshinone IIA Inhibits Epithelial-to-mesenchymal Transition Through Regulating β-arrestin1 Mediated β-catenin Signaling Pathway in Colorectal Cancer

2020 ◽  
Author(s):  
Qing Song ◽  
Liu Yang ◽  
Zhifen Han ◽  
Xinnan Wu ◽  
Ruixiao Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Nude Mice ◽  
Epithelial To Mesenchymal Transition ◽  
Tanshinone Iia ◽  
Mesenchymal Transition

Abstract Background: Tanshinone IIA (Tan IIA) is a major active ingredient extracted from Salvia miltiorrhiza, which has been proved to inhibit metastasis of various cancers including colorectal cancer (CRC). However, the detailed mechanisms of Tan IIA against CRC metastasis are not well explored. Epithelial-to-mesenchymal transition (EMT) exerts an important regulatory role in CRC metastasis, and our previous mechanism studies demonstrated that β-arrestin1 could regulate CRC EMT partly through β-catenin signaling pathway. Therefore, in this work we investigated whether Tan IIA could regulate CRC EMT through β-arrestin1-mediated β-catenin signaling pathway in vivo and in vitro.Methods: The nude mice tail vein metastasis model was established to observe the effect of Tan IIA on CRC lung metastasis in vivo. The lung metastasis was evaluated by living animal imaging and hemaoxylin-eosin staining. The migratory ability of CRC cells in vitro were measured by transwell and wound healing assays. The protein expression and cellular localization of β-arrestin1 and β-catenin were characterized by immunofluorescence staining and western blot. The β-catenin signaling pathway related proteins and EMT associated proteins in CRC cells were detected by western blot and immunohistochemistry. Results: Our results showed that Tan IIA inhibited the lung metastases of CRC cells in vivo and extended the survival time of nude mice. In vitro, Tan IIA increased the expression of E-cadherin, decreased the secretion of Snail, N-cadherin and Vimentin, thus suppressed EMT and the migratory ability of CRC cells. Further study found the mechanism involving in Tan IIA regulating EMT and metastasis, referring to the suppression of β-arrestin1 expression, reduction of β-catenin nuclear localization, thereby the decreased activity of β-catenin signaling. Conclusion: Our data revealed a new mechanism of Tan IIA on the suppression of EMT and metastasis in CRC via β-arrestin1-mediated β-catenin signaling pathway, and provided support for Tan IIA as anti-metastatic agents in CRC.

scholarly journals BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil

2019 ◽  
Vol 11 ◽  
pp. 175883591987897 ◽  
Author(s):  
Yi Jer Tan ◽  
Yeuan Ting Lee ◽  
Sven H. Petersen ◽  
Gurjeet Kaur ◽  
Koji Kono ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Combined Treatment ◽  
Single Treatment ◽  
Combined Treatments ◽  
Combination Treatments ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Tumour Proliferation

Background: This study aims to investigate the combination effect of a novel sirtuin inhibitor (BZD9L1) with 5-fluorouracil (5-FU) and to determine its molecular mechanism of action in colorectal cancer (CRC). Methods: BZD9L1 and 5-FU either as single treatment or in combination were tested against CRC cells to evaluate synergism in cytotoxicity, senescence and formation of micronucleus, cell cycle and apoptosis, as well as the regulation of related molecular players. The effects of combined treatments at different doses on stress and apoptosis, migration, invasion and cell death mechanism were evaluated through two-dimensional and three-dimensional cultures. In vivo studies include investigation on the combination effects of BZD9L1 and 5-FU on colorectal tumour xenograft growth and an evaluation of tumour proliferation and apoptosis using immunohistochemistry. Results: Combination treatments exerted synergistic reduction on cell viability on HCT 116 cells but not on HT-29 cells. Combined treatments reduced survival, induced cell cycle arrest, apoptosis, senescence and micronucleation in HCT 116 cells through modulation of multiple responsible molecular players and apoptosis pathways, with no effect in epithelial mesenchymal transition (EMT). Combination treatments regulated SIRT1 and SIRT2 protein expression levels differently and changed SIRT2 protein localization. Combined treatment reduced growth, migration, invasion and viability of HCT 116 spheroids through apoptosis, when compared with the single treatment. In addition, combined treatment was found to reduce tumour growth in vivo through reduction of tumour proliferation and necrosis compared with the vehicle control group. This highlights the potential therapeutic effects of BZD9L1 and 5-FU towards CRC. Conclusion: This study may pave the way for use of BZD9L1 as an adjuvant to 5-FU in improving the therapeutic efficacy for the treatment of colorectal cancer.

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