Dual Targeting of the Epidermal Growth Factor Receptor Using the Combination of Cetuximab and Erlotinib: Preclinical Evaluation and Results of the Phase II DUX Study in Chemotherapy-Refractory, Advanced Colorectal Cancer

2012 ◽  
Vol 30 (13) ◽  
pp. 1505-1512 ◽  
Author(s):  
Andrew J. Weickhardt ◽  
Tim J. Price ◽  
Geoff Chong ◽  
Val Gebski ◽  
Nick Pavlakis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Growth Factor Receptor ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Colon Cancer Cell Lines ◽  
Epidermal Growth

Purpose This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). Patients and Methods The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m2 as a loading dose and then weekly cetuximab 250 mg/m2 with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. Results Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%). Conclusion The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.

scholarly journals MicroRNA silencing of CNN1 and CNN2 protein family members regulates biology processes in colorectal cancer by targeting the p53 signal pathway

2020 ◽  
Author(s):  
Fuda Huang ◽  
Mingwei Wei ◽  
Anmin Wang ◽  
Ya Zhang ◽  
Zebang Qin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Expression Levels ◽  
Colon Cancer Cell Lines ◽  
Cancer Tissues

Abstract BackgroundCalponin was first defined as a striated muscle troponin T-like protein that binds actin thin filaments to regulate smooth muscle contraction. There are few studies of CNN1 and CNN2 in colorectal cancer, and the roles these two genes play in colorectal cancer cell lines and the mechanisms by which they act are unknown.MethodsWe used immunohistochemistry to identify expression of the two genes in the cancer tissues. RT-PCR was used to measure expression levels of microRNA. W performed western blots to measure changes in signaling pathways in the context of expression interference.Meanwhile, the same method was used to measure binding relationship between the two genes and key pathway proteins. To determine the relationship between microRNA and gene mRNA, we used the reporter gene method. We used the chi-square and t-test methods to analyze the significance and correlations of the data.Results and conclusionsExpression levels of CNN1 were lower in colon cancer tissues than in normal mucosal tissues. After downregulating CNN1, the cell cycle in colon cancer cell lines progressed quickly, and the expression of related pathway proteins also increased. Expression levels of CNN2 were higher in colon cancer tissues, and its downregulation significantly inhibited cell cycle progression in colon cancer cell lines. We confirmed correlations between the expression of microRNA and CNN2 using data analysis.Bars indicate ± standard errors.*p < 0.05; **p < 0.01 compared with the control. The inhibition of the expression of CNN2 mRNA using microRNA was confirmed using western blot. The combination of the two at the mechanism level was also demonstrated using the reporter gene method.

scholarly journals Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines

2012 ◽  
Vol 10 (1) ◽  
pp. 109 ◽  
Author(s):  
Sebastian Gnosa ◽  
Yang-Mei Shen ◽  
Chao-Jie Wang ◽  
Hong Zhang ◽  
Johannes Stratmann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Colon Cancer Cell Lines ◽  
Colorectal Cancer Patients

scholarly journals P08.02 Berberine-loaded liposome formulation enhance the phagocytic activity of liposomal imiquimod towards colon cancer cell lines

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A50.1-A50
Author(s):  
M Mianowska ◽  
M Zaremba-Czogalla ◽  
A Zygmunt ◽  
J Gubernator
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Liposomal Formulations ◽  
Colon Cancer Cell Lines

BackgroundColorectal cancer is the third most commonly diagnosed malignant tumor, taking fourth place in terms of cause of cancer deaths worldwide.1 Unfortunately, the ability of the immune system to distinguish its own from foreign cells is often limited. One of the overexpressed receptors is receptor CD47 - widely distributed glycoprotein on the cell surface of various kind of tumors. It plays a role as ‘don’t eat me’ signal by binding with receptor SIRPα, presents on the cell surface of macrophages.2 Calreticulin, protein occurring on the surface of tumor cells and phagocytes, acts as protein with pro-phagocytic properties. Several natural bioactive substances are predicted to induce immunogenic cell death by translocation calreticulin on the surface of cancer cells which significantly increases the efficiency of their phagocytosis. Moreover, one of the well-known TLR-7 receptor agonists - imiquimod, is involved in phosphorylation of Bruton’s tyrosine kinase leading to the appearance of calreticulin on the surface of macrophages, which increases the efficiency of phagocytosis of tumor cells.3 Combination therapy composed of berberine and imiquimod can be highlighted as effective immunotherapy for colon cancer. However, such an approach remains very limited. Liposomes can serve as promising carriers for targeting delivery and controlled release of anti-cancer agents.Material and MethodsLiposomes were prepared by the thin-film hydration method followed by extrusion. Human colon cancer cell line (LS180 I SW620) and human monocytic cell line (THP-1) were used for experiments. Calreticulin was detected by using confocal microscopy.ResultsThe work presented aimed to develop novel liposomal formulations of berberine and imiquimod which were examined for their efficacy in combination against colorectal cancer cell lines. Liposomal formulations of both compounds were successfully prepared using active loading method with different pH generating agents. All loading methods showed desired characteristics in terms of mean liposome size and polydispersity. The encapsulation efficiency was higher than 95% for almost all used formulations. The in vitro study proved cytotoxicity of berberine loaded liposomal formulations on tested colon cancer cell lines. The results of the immunofluorescence staining indicated that the both compounds triggered calreticulin on the cell surface (colon cancer or macrophages).ConclusionsThe combination of both substances in the liposomal form may generate a synergistic effect on phagocytosis of colon cancer cells.ReferencesArnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683–691.Sick E, Jeanne A, Schneider C, Dedieu S, Takeda K, Martiny L. CD47 update: a multifaceted actor in the tumor microenvironment of potential therapeutic interest, Br J Pharmacol 2012, 167(7):1415–30.M. Feng, et al., Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk. PNAS 2015;112( 7):2145–2150.Disclosure InformationM. Mianowska: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; National Science Center, Poland. M. Zaremba-Czogalla: None. A. Zygmunt: None. J. Gubernator: None.

scholarly journals SLC7A5 Promotes Colorectal Cancer Progression by Regulating Cell Cycle and Migration

2021 ◽  
Author(s):  
Baiyou Tang ◽  
Lihua Zhang ◽  
Jing Yu ◽  
Mingjing Peng ◽  
Yu Cheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Functional Enrichment ◽  
Public Database ◽  
Colon Cancer Cell Lines

Abstract Background: Solute carrier family 7 member 5 (SLC7A5) was identified highly expressed and as a key participant in various tumor development; however, the role it played in colorectal cancer remains unclear. Methods and Results: In the current study, the expression of SLC7A5 were systematically mined in public databases and validated by real-time PCR in colon cancer and normal tissues. And then, the co-expression and pathway analysis got from public database, which indicated the potential influence of SLC7A5 for the etiology of colorectal cancer, were evaluated in the colon cancer cell lines by loss of SLC7A5 function experiment, flow cytometry, western blot, and wound healing assay. The results showed that the mRNA expression of SLC7A5 was significantly higher in colorectal cancer tissues than that in the non-tumor controls for GEO and TCGA datasets as well as 40 pairs of Xiangya clinical samples. The functional enrichment analysis based on public database showed that the pathways enriched most were cell cycle and epithelial-to-mesenchymal transition (EMT), and Cyclin D1 (CCND1) were the only gene that had a significant positive correlation with SLC7A5. Loss of SLC7A5 function in colon cancer cell lines could arrest cell cycle at G1 phase by down-regulating CCND1 and CDK2 protein expression, and may reduce cell migration by reversing EMT though upregulation of E-Cadherin and downregulation of zonula occludens-1. Conclusion: SLC7A5 is likely associated with the progression of colon cancer.

scholarly journals Cysteine-Rich Intestinal Protein 1 Silencing Inhibits Migration and Invasion in Human Colorectal Cancer

2017 ◽  
Vol 44 (3) ◽  
pp. 897-906 ◽  
Author(s):  
Guoyang He ◽  
Liyuan Zou ◽  
Lin Zhou ◽  
Peiqiong Gao ◽  
Xinlai Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Colon Cancer Cell Lines

Background/Aims: Cysteine-rich intestinal protein 1 (CRIP1), a member of the LIM/double zinc finger protein family, is abnormally expressed in several tumour types. However, few data are available on the role of CRIP1 in cancer. In the present study, we aimed to investigate the expression profile and functions of CRIP1 in colorectal cancer. Methods: To examine the protein expression level of CRIP1, immunohistochemistry (IHC) was performed on 56 pairs of colon cancer tissue samples. Western blotting was performed to investigate CRIP1 protein expression in four colon cancer cell lines. The endogenous expression of CRIP1 was suppressed using short interfering RNAs (siRNAs). Cell proliferation assays were used to determine whether CRIP1 silencing affected cell proliferation. Flow cytometry analysis was used to detect cell apoptosis. The effects of silencing CRIP1 on cell migration and invasion was detected using the transwell and wound-healing assays. Results: IHC analysis showed that protein level of CRIP1 was significantly higher in tumour tissue samples than in paired non-tumour tissue samples and that the CRIP1 level was higher in metastatic tissue samples than in non-metastatic tissue samples. In addition, protein levels of CRIP1 were higher in highly metastatic colon cancer cell lines than in colon cancer cell lines with low metastasis. Further, CRIP1 silencing had no effect on cell proliferation or apoptosis in SW620 and HT29 cells. CRIP1 silencing suppressed cell migration and invasion obviously in SW620 and HT29 cells. Conclusion: The present study provides new evidence that abnormal expression of CRIP1 might be related to the degree of metastasis in colorectal cancer and that CRIP1 silencing could effectively inhibit migration and invasion during colorectal cancer development. These findings might aid the development of a biomarker for colon cancer prognosis and metastasis, and thus help to treat this common type of cancer.

scholarly journals Clinicopathological and prognostic significance of TM4SF5 in colorectal cancer

2021 ◽  
Author(s):  
Zhongbei Yu ◽  
Jun Feng ◽  
Yulan Zhu ◽  
Xiaolu Xie ◽  
Hao Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prognostic Value ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Biological Behavior ◽  
Migration And Invasion ◽  
Colon Cancer Cell Lines

Abstract Background Transmembrane 4 L six family member 5 (TM4SF5) has been found to play a vital role in the cancer process, but the relationship between TM4SF5 and colorectal cancer remains unclear. Therefore, the present study aimed to investigate the clinical and prognostic value of TM4SF5 in colorectal cancer (CRC). Methods Immunohistochemistry and RT-qPCR were used to identify the clinical significance and prognostic value of TM4SF5 expression in colon cancer. The expression of TM4SF5 was knocked down using the siRNA method to evaluate the role of TM4SF5 in regulating the biological behavior of colon cancer cell lines. Results The immunohistochemistry study revealed that the expression of TM4SF5 in human colorectal cancer tissues was significantly higher than that in adjacent normal tissues (P < 0.0001). However, there was no correlation between the expression of TM4SF5 and the clinicopathological features of these patients. The RT-qPCR analysis revealed that the mRNA expression of TM4SF5 was higherin colon cancer cell lines than in normal cells (P < 0.05). The survival analysis revealed that the overall survival (OS) rate of patients with a low expression of TM4SF5 was significantly higher, when compared to patients with a high expression of TM4SF5 (P = 0.048). The COX model revealed that the expression of TM4SF5 (P < 0.001) and clinical stage (P = 0.025) can be used as independent prognostic factors for patients with colon cancer. In addition, the knockdown of TM4SF5 in colon cancer cell lines LoVo, SW480, RKO and HCT-116 significantly reduced the ability of cells (such as proliferation, migration and invasion). Conclusion The present results indicate that the increase in TM4SF5 expression in human colon cancer is associated with cancer progression and poor survival, and that its intervention can be an important therapeutic strategy against colon cancer.

Isolation of Cardamonin and Pinostrobin Chalcone from the Rhizomes of Boesenbergia rotunda (L.) Mansf. and their Cytotoxic Effects on H-29 and MDA-MB-231 Cancer Cell Lines

2019 ◽  
Vol 9 (4) ◽  
pp. 341-348 ◽  
Author(s):  
Ibrahim Awad Mohammed ◽  
Muhammad Nadeem Akhtar ◽  
Foo Jhi Biau ◽  
Yin Sim Tor ◽  
Seema Zareen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colon Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Chemical Constituents ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Colon Cancer Cell Lines ◽  
Ht 29

<P>Background: Breast cancer and human colon cancer are the most common types of cancer in females and males, respectively. Breast cancer is the most common type of cancer after lung and colon cancers. Natural products are an important source for drug discovery. Boesenbergia rotunda (L.) Mansf. is commonly known as finger root, belonging to the Zingiberaceae family. </P><P> Objective: The aim of this study to isolate some natural compounds from the rhizomes of B. rotunda (L.) Mansf., and to investigate their cytotoxicity against the human triple-negative breast cancer cell (MDA-MB-231) and HT-29 colon cancer cell lines. </P><P> Methods: The dried rhizomes of B. rotunda were extracted with methanol. The methanolic extract was further used for solvent-solvent extraction. Bioassay-guided extraction and isolation of the rhizomes of the B. rotunda exhibited cytotoxic properties of hexane and dichloromethane fractions. </P><P> Results: Six major chemical constituents, pinostrobin (1), pinostrobin chalcone (2), cardamonin (3), 4,5-dihydrokawain (4), pinocembrin (5), and alpinetin (6) were isolated from the rhizomes of the B. rotunda. All the chemical constituents were screened against the human triple-negative breast cancer cell (MDA-MB-231) and HT-29 colon cancer cell lines. The compound cardamonin (3) (IC50 = 5.62&#177;0.61 and 4.44&#177;0.66 &#181;g/mL) and pinostrobin chalcone (2), (IC50 = 20.42&#177;2.23 and 22.51&#177;0.42 μg/mL) were found to be potent natural cytotoxic compounds against MDA-MB-231 and HT-29 colon cancer cell lines, respectively. </P><P> Conclusion: Cardamonin (3) and pinostrobin chalcone (2) were found to be the most potential natural compounds against breast cancer cell line MDA-MB-231 and colon cancer HT-29 cell line.</P>

scholarly journals Anticancer effects of bifidobacteria on colon cancer cell lines

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zeinab Faghfoori ◽  
Mohammad Hasan Faghfoori ◽  
Amir Saber ◽  
Azimeh Izadi ◽  
Ahmad Yari Khosroushahi
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Colon Cancer Cell ◽  
Rt Pcr ◽  
Anticancer Effects ◽  
Colon Cancer Cell Lines ◽  
Apoptotic Genes

Abstract Background Colorectal cancer (CRC), with a growing incidence trend worldwide, is resistant to apoptosis and has uncontrolled proliferation. It is recently reported that probiotic microorganisms exert anticancer effects. The genus Bifidobacterium, one of the dominant bacterial populations in the gastrointestinal tract, has received increasing attention because of widespread interest in using it as health-promoting microorganisms. Therefore, the present study aimed to assess the apoptotic effects of some bifidobacteria species on colon cancer cell lines. Methods The cytotoxicity evaluations performed using MTT assay and FACS-flow cytometry tests. Also, the effects of five species of bifidobacteria secretion metabolites on the expression level of anti- or pro-apoptotic genes including BAD, Bcl-2, Caspase-3, Caspase-8, Caspase-9, and Fas-R studied by real-time polymerase chain reaction (RT-PCR) method. Results The cell-free supernatant of all studied bifidobacteria significantly decreased the survival rates of colon cancer cells compared with control groups. Flow cytometric and RT-PCR results indicated that apoptosis is induced by bifidobacteria secretion metabolites and the mechanism for the action of bifidobacteria species in CRC prevention could be down-regulation and up-regulation of anti-apoptotic and, pro-apoptotic genes. Conclusions In the present study, different bifidobacteria species showed anticancer activity on colorectal cancer cells through down-regulation and up-regulation of anti-apoptotic and pro-apoptotic genes. However, further studies are required to clarify the exact mechanism of apoptosis induction by bifidobacteria species.

scholarly journals Reactivity of Monoclonal Antibodies Directed against Lung Cancer Antigens with Human Lung, Breast and Colon Cancer Cell Lines

1993 ◽  
Vol 11 (5-6) ◽  
pp. 225-237
Author(s):  
Udo Schumacher ◽  
Dhia Mukthar ◽  
Thomas Schenker
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Colon Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colon Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Cancer Antigens ◽  
Colon Cancer Cell Lines

A panel of monoclonal antibodies (n=72 including controls) directed against lung cancer antigens was screened immunohistochemically against a panel of seven human lung cancer cell lines (including small cell carcinoma, squamous cell carcinoma, adenocarcinoma and mesothelioma), six human breast cancer cell lines and one human colon cancer cell line, The majority of the antibodies (n=42) reacted also with antigens present on breast and colon cancer cell lines, This cross reactivity especially between lung and breast cancer cell lines is not altogether unexpected since antigens common to breast and lung tissue including their neoplasms such as MUC1 antigen have been described, Our results indicate that epitopes shared by lung and breast cancers are probably more common than previously thought. The relevance for prognosis and therapy of these shared antigens, especially as disease markers in breast cancer, has to be investigated.

Sign in / Sign up

Export Citation Format

Share Document