Effects In Colorectal Cancer Research Articles

Type Iγ phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer

BackgroundEmerging evidence suggests that metabolic alterations are a hallmark of cancer cells and contribute to tumor initiation and development. Cancer cells primarily utilize aerobic glycolysis (the Warburg effect) to produce energy and support anabolic growth. The type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) is profoundly implicated in tumorigenesis, however, little is known about its role in reprogrammed energy metabolism. MethodsLoss- and gain-of-function studies were applied to determine the oncogenic roles of PIPKIγ in colorectal cancer. Transcriptome analysis, real-time qPCR, immunohistochemical staining, Western blotting, and metabolic analysis were carried out to uncover the cellular mechanism of PIPKIγ. FindingsIn this study, we showed that PIPKIγ was frequently upregulated in colorectal cancer and predicted a poor prognosis. Genetic silencing of pan-PIPKIγ suppressed cell proliferation and aerobic glycolysis of colorectal cancer. In contrast, the opposite effects were observed by overexpression of PIPKIγ_i2. Importantly, PIPKIγ-induced prolific effect was largely glycolysis-dependent. Mechanistically, PIPKIγ facilitated activation of PI3K/Akt/mTOR signaling pathways to upregulate c-Myc and HIF1α levels, which regulate expression of glycolytic enzymes to enhance glycolysis. Moreover, pharmacological inhibition by PIPKIγ activity with the specific inhibitor UNC3230 significantly inhibited colorectal cancer glycolysis and tumor growth. InterpretationOur findings reveal a new regulatory role of PIPKIγ in Warburg effect and provide a key contributor in colorectal cancer metabolism with potential therapeutic potentials. FundNational Key Research and Development Program of China, Outstanding Clinical Discipline Project of Shanghai Pudong, Natural Science Foundation of China, and Science and Technology Commission of Shanghai Municipality.

Effects of 17β-estradiol on colorectal cancer development after azoxymethane/dextran sulfate sodium treatment of ovariectomized mice

Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERβ) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.

Phytochemical Modulation of MiRNAs in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of death in the United States. Chemotherapy and radiotherapy are some of the most commonly used treatments, but are often associated with severe side effects, and are not entirely curative. It is therefore important to consider other preventative treatment options. Phytochemicals are naturally occurring bioactive compounds which have been shown to play a role in cancer prevention and treatment, especially in regards to a person’s lifestyle and diet. Recent evidence has shown that phytochemicals may exert their chemopreventative effects by targeting micro RNAs (miRNAs), which regulate the downstream expression of tumor suppressors and oncogenes. MiRNAs are small, endogenous, noncoding RNAs that regulate several biological processes through post-translational regulation. The dysregulation of miRNA expression has been shown to be associated with colorectal cancer. In this review, we will summarize and discuss several phytochemicals, which have been shown to exert chemopreventative effects in colorectal cancer by the modulation of miRNA expression.

A Ras destabilizer KYA1797K overcomes the resistance of EGFR tyrosine kinase inhibitor in KRAS-mutated non-small cell lung cancer

The epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are widely used for treatment of non-small cell lung cancer (NSCLC), but they have shown limited efficacy in an unselected population of patients. The KRAS mutations, which are identified in approximately 20% of NSCLC patients, have shown to be associated with the resistance to the EGFR tyrosine kinase inhibitors (TKIs). Currently, there is no clinically available targeted therapy which can effectively inhibit NSCLC tumors harboring KRAS mutations. This study aims to show the effectiveness of KYA1797K, a small molecule which revealed anti-cancer effect in colorectal cancer by destabilizing Ras via inhibiting the Wnt/β-catenin pathway, for the treatment of KRAS-mutated NSCLC. While erlotinib fail to have anti-transforming effect in NSCLC cell lines harboring KRAS mutations, KYA1797K effectively inhibited the Ras-ERK pathway in KRAS-mutant NSCLC cell lines. As a result, KYA1797K treatment suppressed the growth and transformation of KRAS mutant NSCLC cells and also induced apoptosis. Furthermore, KYA1797K effectively inhibited Kras-driven tumorigenesis in the KrasLA2 mouse model by suppressing the Ras-ERK pathway. The destabilization of Ras via inhibition of the Wnt/β-catenin pathway is a potential therapeutic strategy for KRAS-mutated NSCLC that is resistant to EGFR TKI.

Chinese Herbal Medicines Facilitate the Control of Chemotherapy-Induced Side Effects in Colorectal Cancer: Progress and Perspective.

Side effects, including nausea, vomiting, mucositis, peripheral neuropathy, and diarrhea, have been frequently reported in colorectal cancer (CRC) patients undergoing chemotherapy. Chinese Herbal Medicines (CHMs) display distinct clinical outcomes, as a result, they have been increasingly used as an adjuvant therapy to manage chemotherapy-induced side effects. In this review, we aim to intensively explore the molecular mechanisms of CHMs, underline the significance of CHMs in mitigating the side effects induced by chemotherapy, and examine the necessary studies required to understand the role of CHMs in alleviating chemotherapy-induced side effects. Specifically, ginger, Astragali Radix, and Liujunzi Decoction have been verified to ameliorate nausea and vomiting. Banxia Xiexin Decoction and Huangqin Decoction have been confirmed to be beneficial to mucositis and delayed-onset of diarrhea. Moreover, Niuche Shenqi Wan, Guilong Tongluo Decoction, Huangqi Guizhi Wuwu Decoction, and tumeric have been found to display potential therapeutic effects for preventing the genesis and development of peripheral neurotoxicity. These findings have further emphasized the pivotal role of CHMs in improving the outcomes of chemotherapy-induced side effects in CRC. Nonetheless, more molecular evidence is required to comprehensively understand and more appropriately apply CHMs in routine clinical practice for CRC.

Oral Administration of Liposome-Apatinib and Locally Delivery of Docetaxel/MPEG-PCL by Fibrin Glue Synergistically Improve Therapeutic Effect in Colorectal Cancer.

Colorectal cancer is one of the most common and malignant cancer in the world wide. Recently, combination of target therapy and chemotherapy has generated new promise for colorectal cancer. Apatinib mesylate is a novel and highly selective VEGFR-2 inhibitor, presented with an outstanding activity of anti-angiogensis, which has the potential for treating various tumors. As a traditional chemotherapeutic drug, docetaxel (Taxotere) is a widely used semisynthetic taxoid in solid tumors. In this study, Liposome and Methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) were constructed as drug delivery system for the delivery of apatinib (Lipo-Apa) and docetaxel (DOC/M), respectively. Co-administration of Lipo-Apa and DOC/M showed synergistically effects on inhibiting cell proliferation and inducing cell apoptosis of CT26 cells in vitro. Moreover, fibrin glue, as a biocompatible adherent hemostat, was used as a kind of vehicle for locally delivery of DOC/M in animal models, for achieving locally high concentration and prolonging releasing time. Combination of Lipo-Apa by gavage and locally delivery of DOC/M showed significantly improved anti-tumor activity in a subcutaneous xenograft model as well as in the abdominal metastasis model of colorectal cancer. In addition, promoted tumor apoptosis, inhibited proliferation and decreased tumor angiogenesis were presented by the co-administration. Finally, our study suggested that combination of oral administration of Lipo-Apa and locally delivery of DOC/M by fibrin glue, has the potential to be applied clinically in colorectal cancer therapy.

Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin

Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.

The incorporation of Pterodon pubescens fruit oil into optimized nanostructured lipid carriers improves its effectiveness in colorectal cancer

The 23 full factorial design was used to optimize the development of nanostructured lipid carriers (NLCs) containing P. pubescens fruit oil by the melt-emulsification method. The effects of the type of solid lipid, concentration of Phospholipon® 80H and type of aqueous surfactant in parameters such as particle size, polydispersity index (PI), zeta potential (ZP), total content (TC), and encapsulation efficiency (EE) of vouacapans were evaluated. The preparation method of the NLCs was appropriate as the chemical profile of the oil remained unchanged before and after the development process. The studied factors proved to affect the NLCs quality factors at different significant levels. The NLC that presented the best results was the formulation F4, which was produced with Precirol® ATO 5, 0.5% Phospholipon® 80H, and PEG-40 hydrogenated castor oil/sorbitan oleate. The optimized formulation showed small and spherical particles of 94.47 ± 2.05 nm, a PI of 0.197 ± 0.003, ZP less than –30 mV, and excellent physical stability after dispersion analysis. In addition, high values (>98%) of the TC and EE of vouacapans were obtained. X-ray diffraction, Fourier transform Raman spectroscopy and differential scanning calorimetry analysis were also performed. The results suggested that lipids may be partially recrystallized and less ordered in NLCs and that between the P. pubescens oil and lipid matrix an interaction may exist. The P. pubescens fruit oil presented in vitro cytotoxicity to HT-29 cells, with CC50 of 273.47 μg/mL, and was more cytotoxic when incorporated into NLCs (CC50 of 154.19 μg/mL), which justifies the use of such technology in the development of novel phytopharmaceutical products.

Abstract 5923: CD133-targeted oncolytic adenovirus exhibits anti-tumor effect in colorectal cancers, and its combination with irradiation inhibits liver metastasis

Abstract Colorectal cancer (CRC) is the third most common cancer in the world, and about 50% of patients relapse after treatment. Cancer stem cells (CSCs) have contribution to recurrence, metastasis and chemotherapy resistant of CRC. CD133 (Prominin-1), a member of the transmembrane glycoprotein family, is a marker of CSCs in several cancers including CRC: its expression correlates with recurrence, metastases and chemotherapy resistance, as well as poor prognosis in CRC. It is therefore reasonable to develop a CSC-directed CRC therapeutic strategy by employing CD133as a target molecule. Recently, we have established a method for isolating transductionally-targeted infectivity-selective adenovirus by high-throughput screening. Using this adenovirus library screening system, we isolated the CD133-specific Oncolytic Adenovirus (OAd) and tested the oncolytic activity of CD133-targeted OAd (CD133-OAd) in both in vitro and in vivo, with and without irradiation which induces CD133 expression. The infectivity-selective OAd (ISOAd) with CD133-targeting motif (TYML motif) selectively infected CD133+ CRC cell lines and lysed them efficiently. In the context of modulation of stemness, CD133-OAd inhibited colony formation in vitro. In tumor formation assay in nude mice, treatment with CD133-OAd prior to tumor inoculation inhibited the establishment of tumor of CD133+ CRC cell lines. Intra-tumor (i.t.) administration of CD133-OAd into established subcutaneous tumor exhibited significantly stronger antitumor effect compared to OAd without targeting. We have reported that the irradiation increases CD133 expression in CRC cells, and the replication of CD133-OAd increased significantly after irradiation. In athymic nude mice, treatment of irradiated cells with CD133-OAd abolished tumor-forming capacity, compared to cells without irradiated and cells treated with radiation alone (5% vs 94% and 5% vs 73% respectively, p<0.0001). When the antitumor effect of CD133-OAd was analyzed on subcutaneously established tumors, treatment with radiation and CD133-OAd significantly reduced tumor growth compared to no treatment and treatment with radiation only (both p<0.0001). In addition to the effect on the main tumor, CD133-OAd suppressed liver metastasis of CRC. The mice injected with human CRC cells pretreated with CD133-OAd combined with irradiation had significantly lower incidence of liver metastasis compared with the untreated control group or the groups received irradiation or CD133-OAd treatment alone. Our CD133-targeted ISOAd is effective for cytotoxic killing, reduces tumor formation, and mitigates tumor growth in radiation resistant CRC cells. This targeted OAd therapy may be applicable to address therapeutic resistance and prevent the establishment of recurrent colorectal cancer. Citation Format: Jing Li Huang, Mizuho Sato-Dahlman, Kari Jacobsen, Masato Yamamoto. CD133-targeted oncolytic adenovirus exhibits anti-tumor effect in colorectal cancers, and its combination with irradiation inhibits liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5923.

<i>Gamellia sinensis O.Ktze</i> extract shows anti-colorectal cancer activity via MAPK/ERK signaling pathway

Purpose: To investigate the therapeutic effects of Gamellia sinensis O.Ktze extract (GSOE) on colorectal cancers, as well as the underlying mechanisms.Methods: The effect of GSOE on colorectal cancer cells HCT-116 or Caco-2 growth was tested, and then the apoptosis and invasion was analyzed by MTT, flow cytometry and Transwell assay in vitro. Next, the mice received three doses (200, 400 or 800 mg/kg/day, gastric perfusion) of GSOE to evaluate its effects on tumor growth. Lung metastasis in mouse xenograft models which were inoculated with HCT-116 or Caco-2 cells were also investigated. The expression of p-ERK and p-MEK were evaluated by western blot analysis in HCT-116 and Caco-2 cells with or without GSOE treatment in vitro.Result: GSOE significantly inhibited colorectal cancer cell growth and induced apoptosis or cell cycle arrest at G1- and S-phases in HCT-116 cells and Caco-2 cells in a dose-dependent manner. Moreover, GSOE effectively retarded tumor cell migration and invasion through ERK/MAPK signaling pathway suppression.Conclusion: These findings demonstrate that GSOE has an anti-tumor effect in colorectal cancer by inactivating ERK/MAPK signaling pathway.Keywords: Gamellia sinensis O.Ktze, Colorectal cancer, Invasion, Apoptosis, Cell cycle arrest ERK, MAPK

Survival and glycemic control in patients with colorectal cancer and diabetes mellitus.

e18755Background: This study examined the impact of diabetes mellitus (DM) on survival in colorectal cancer patients, and the effect of colorectal cancer on glycemic control. Methods: Colorectal ca...

AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status.

BackgroundBRAF mutation is associated with poor clinical outcome of patients with malignant tumours, and mediates resistance to chemotherapy and targeted therapy. This study aimed to determine whether V600E mutant and wild type BRAF colorectal cancers exhibit distinct sensitivities to the dual BRAF inhibitor AZ304.MethodsKinase activity was assessed by the AlphaScreen assay. Then, MTT assay, EdU assay, colony-formation assay and Western blot were performed to evaluate the anti-tumour effects of AZ304 in vitro. In vivo efficacy was investigated by xenograft analysis and immunohistochemistry.ResultsAZ304 exerted potent inhibitory effects on both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF, with IC50 values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of human cancer cell lines with different BRAF and RAS genetic statuses. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. In addition, the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independently of BRAF mutational status.ConclusionsThe BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo.

Molecular targets of Chinese herbs: a clinical study of metastatic colorectal cancer based on network pharmacology

Increasing evidence has shown that Chinese herbal medicine (CHM) has promising therapeutic effects in colorectal cancer (CRC); however, the active ingredients and potential targets remain unclear. In this study, we aimed to investigate the relative molecular targets of the Chinese herbs that have been found effective in treating metastatic CRC (mCRC) based on clinical data and network pharmacology. In multivariate analysis CHM resulted an independent prognostic factor. The hazard ratio was 0.103 (95% confidence interval = 0.064–0.164; P < 0.001). Compared with the non-CHM group, the median survival time of the CHM group was also improved (40 versus 12 months; P < 0.001). Eighteen out of 295 herbs showed significant correlation with survival results (P < 0.05). Bioinformatics analysis indicated that the 18 herbs realize anti-CRC activity mainly through suppressing the proliferative activity of ERBB2, peroxisome proliferator-activated receptor gamma, and retinoid X receptor, suppressing angiogenesis via inhibition of VEGFR and VEGFA expression, inhibiting the phosphatidylinositol-3-kinase/AKT1 signaling pathway directly through SRC and AKT1, and reducing tumor necrosis factor-induced inflammation.

Sa1200 - Cd133-Targeted Oncolytic Adenovirus Exhibits Anti-Tumor Effect in Colorectal Cancers, and Its Combination with Irradiation Inhibits Liver Metastasis

Sa1200 - Cd133-Targeted Oncolytic Adenovirus Exhibits Anti-Tumor Effect in Colorectal Cancers, and Its Combination with Irradiation Inhibits Liver Metastasis

Effects of Recombinant Circularly Permuted Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) (Recombinant Mutant Human TRAIL) in Combination with 5-Fluorouracil in Human Colorectal Cancer Cell Lines HCT116 and SW480.

BackgroundCircularly permuted tumor necrosis factor-related apoptosis-inducing ligand, a mutant form of tumor necrosis factor-related apoptosis-inducing ligand, is an effective antitumor cytokine. However, its antitumor effect in colorectal cancer is unclear. This study assessed the antitumor effect of circularly permuted tumor necrosis factor-related apoptosis-inducing ligand alone or with 5-fluorouracil in colorectal cancer cells in vitro and explored the underlying mechanisms.Material/MethodsWe used the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay to analyze cell proliferation inhibition. The apoptotic effects of circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, 5-fluorouracil, or both in human colorectal cancer cells were evaluated using flow cytometry. Furthermore, the levels of apoptosis-related proteins were examined by Western blotting.ResultsCompared to either agent alone, cotreatment with 5-fluorouracil and circularly permuted tumor necrosis factor-related apoptosis-inducing ligand showed obvious antitumor effects and induced significant apoptosis of colorectal cancer cells. 5-Fluorouracil enhanced circularly permuted tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by increasing death receptor 4 and 5 levels in HCT116 cells, but only of death receptor 4 in SW480 cells. Moreover, 5-fluorouracil plus circularly permuted tumor necrosis factor-related apoptosis-inducing ligand increased apoptosis-related protein levels such as cleaved caspase-3, caspase-8, and poly-ADP-ribose polymerase and downregulated that of the survival protein B-cell lymphoma-extra-large. Pretreatment with the pan-caspase inhibitor, z-VAD-FMK, attenuated the caspase-dependent apoptosis induced by circularly permuted tumor necrosis factor-related apoptosis-inducing ligand alone or combined with 5-fluorouracil.ConclusionsCotreatment with 5-fluorouracil and circularly permuted tumor necrosis factor-related apoptosis-inducing ligand showed enhanced antitumor effects on colorectal cancer cells.

Turmeric extract, with absorbable curcumin, has potent anti-metastatic effect in vitro and in vivo

BackgroundCurcumin, a well-studied component in turmeric, exhibits potent antitumor effects in colorectal cancer. Previous studies showed that turmerones raised the accumulation of curcumin inside colonic cells, and curcumin present in turmeric ethanolic extract had enhanced anti-tumor activities in mice. Metastasis accounts for more than 90% colorectal cancer deaths. However, the anti-metastatic effect of turmeric extract on colorectal cancer is still unknown. MethodsIn the present study, colony formation, scratch, transwell and Western blot were used to assess colony formation, motility, migration and underlying mechanisms in vitro, respectively. Anti-tumor and anti-metastatic effects in vivo were investigated using an orthotopic xenograft model. ResultsTurmeric extract exhibited cytotoxic effect, inhibited colony formation, decreased cell motility, migration and epithelial–mesenchymal transitions through regulating multiple pathways including cofilin, FAK/p-Src, AKT, Erk and STAT3 signaling pathways in murine colorectal cancer cells. Furthermore, turmeric extract at 200 mg/kg could decrease colon tumor burden and inhibit liver and lung metastasis in vivo. Treatment of turmeric extract enhanced immunity through T cell stimulation, changed tumor microenvironment, exerted anti-metastatic effects which were shown for the first time in pre-clinical colorectal cancer models. The decrease of immunity after FOLFOX treatment was also firstly demonstrated in mouse model. ConclusionsTurmeric extract was demonstrated for the first time for its anti-tumor and anti-metastatic effects in both colorectal cancer cells and orthotopic mouse model through regulation of multiple targets. These findings strongly suggested the promising use of turmeric extract as chemopreventive or chemotherapeutic agent for colorectal cancer patients with metastasis.

PO-1058: Maintenance BEZ235 following BEZ235 and radiation prolongs therapeutic effect in colorectal cancer

PO-1058: Maintenance BEZ235 following BEZ235 and radiation prolongs therapeutic effect in colorectal cancer

Histamine and Histaminergic Receptors in Colorectal Cancer: From Basic Science to Evidence-based Medicine

Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflammation. Several studies have also emphasized its pro-carcinogenic effect in colorectal cancer (CRC). In fact, increased histamine levels have been observed in CRC and a decreased catabolism of this molecule is typical of colorectal adenomas. Additional data have demonstrated that CRC is characterized by an altered balance of histamine receptors (HRs); in fact, HR1 and HR4 are down-regulated in CRC, while HR2 is overexpressed. Based on this evidence, we reviewed several studies investigating the role of HR2 antagonists (HR2A), such as cimetidine in CRC. From a clinical point of view, HR2A may prolong the survival rates of patients with CRC, and a recent meta-analysis seems to confirm this finding. From a biological perspective, it has been demonstrated that HR2A could have a beneficial effect on CRC for many reasons: i) promotion of peri-tumoral lymphocyte growth and improvement of immune response against the tumor, ii) suppression of adhesion molecules which might favor metastasis, iii) anti-angiogenetic activity (reduction of VEGF), iv) increased production of some cytokines which may counteract tumor growth, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-10 and IL-15. On the contrary, HR1 antagonists did not demonstrate any beneficial effect on CRC. Therefore, it is presumable that histamine could be a relevant player in the development of CRC, but its effect might be mediated by an imperfect homeostasis of its receptors. In this scenario, HR2A could inhibit carcinogenesis whereas HR2 might act as a pro-carcinogenetic, while HR1 and HR4, being suppressed in CRC, may antagonize neoplastic development.

Andrographolide enhanced 5-fluorouracil-induced antitumor effect in colorectal cancer via inhibition of c-MET pathway.

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu) is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro) is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells. In vitro studies showed that Andro synergistically enhanced the anti-proliferation effect of 5-Fu on HCT-116 cells due to increased apoptotic cells. Meanwhile, results of the enzyme linked immunosorbent assay indicated that the level of phosphorylated cellular-mesenchymal to epithelial transition factor (p-MET) was decreased by the combination treatment. Further study suggested that Andro promoted the antitumor effect of 5-Fu by down-regulating the level of p-MET. In conclusion, these results confirmed the synergistic antitumor activity of Andro on CRC and provide evidence for possible clinical application of Andro for enhancing the antitumor effect of 5-Fu in CRC treatment.

TRAIL mutant membrane penetrating peptide alike (TMPPA) TRAIL‑Mu3 enhances the antitumor effects of TRAIL invitro and invivo.

The aim of the present study was to prepare a tumor necrosis factor ligand superfamily member 10 (TRAIL) mutant membrane penetrating peptide alike (TMPPA), TRAIL‑Mu3, and to investigate its antitumor effects in colorectal cancer invitro and invivo. The pMD19/TRAIL plasmid with designed primers was amplified to construct the target gene; it was ligated with an expression plasmid and the expression was confirmed. Subsequently, TRAIL‑Mu3 was purified and further confirmed by western blot analysis. Immunofluorescence analysis was used to detect the distribution of TRAIL‑Mu3 in colorectal cancer cells. In addition, the present study investigated the antitumor effects of TRAIL‑Mu3 on colorectal cancer invitro and invivo. A novel TMPPA, TRAIL‑Mu3, was synthesized in the present study. Following a series of detection experiments, it was confirmed that the TRAIL‑Mu3 gene was obtained and was able to express TRAIL‑Mu3 successfully. The immunofluorescence analysis demonstrated that TRAIL‑Mu3 exhibited a markedly enhanced affinity to the colorectal cancer cell surface. In addition, TRAIL‑Mu3 exerted stronger antitumor effects, compared with TRAIL, on colorectal cancer invitro and invivo.