Impact of preexisting proteinuria on the development of regorafenib-induced problematic proteinuria in real-world metastatic colorectal cancer treatment.

Regorafenib is the first multikinase inhibitor for treating metastatic colorectal cancer (mCRC). Proteinuria is a frequently encountered adverse effect, regardless of prior administration of vascular endothelial growth factor inhibitors. Herein, we aimed to assess the impact of baseline preexisting proteinuria on regorafenib-induced problematic proteinuria during real-world mCRC therapy. Patients with mCRC receiving regorafenib (n = 100) were retrospectively assessed and divided into control and preexisting proteinuria (baseline grade of 1-2) groups. The primary endpoint was the development of grade ≥ 2 (grade ≥ 3 in case of baseline grade 2 patients) proteinuria. Propensity score-matching was performed to confirm the robustness of primary analyses. Defined proteinuria occurred in 30.7 and 57.9% of patients in the control and preexisting proteinuria groups, respectively, with significant differences in the all-patient population (P = 0.01). The preexisting proteinuria group exhibited significant defined proteinuria development within 7 days of regorafenib initiation, grade ≥ 3 symptoms, and treatment suspension owing to proteinuria. Similar results were obtained in the propensity score-matched population. According to multivariate logistic regression analysis, baseline proteinuria was a singular risk factor for defined proteinuria development (adjusted odds ratio; 3.76, 95% confidence interval; 1.45-9.75, P = 0.007). Collectively, our study revealed that patients with preexisting proteinuria develop regorafenib-induced proteinuria degradation.

Banxia Xiexin Decoction delays colitis-to-cancer transition by inhibiting E-cadherin/ß-catenin pathway via Fusobacterium nucleatum FadA.

ETHNOPHARMACOLOGICAL RELEVANCE: Colitis is an important risk factor for the occurrence of colorectal cancer (CRC), and the colonization of Fusobacterium nucleatum (Fn) in the intestines accelerates this transformation process. Banxia Xiexin Decoction (BXD), originating from Shanghanlun, is a classic prescription for treating gastrointestinal diseases. Current researches indicate that BXD can effectively delay the colitis-to-cancer transition, but it is still unclear whether it can inhibit Fn colonization to achieve this delaying effect. AIM OF STUDY: This study explored the effect and mechanism of BXD in inhibiting Fn intestinal colonization to delay colitis-to-cancer transition. MATERIALS AND METHODS: We constructed a mouse model of colitis-to-cancer transition by regularly gavaging Fn combined with azoxymethane (AOM)/dextran sodium sulfate (DSS), and administered BXD by gavage. We monitored the body weight of mice, measured the length and weight of their colons, and calculated the disease activity index (DAI) score. The growth status of colon tumors was observed by hematoxylin and eosin (H&E) staining, and the changes in gut microbiota in each group of mice were detected by 16S rDNA analysis. Immunohistochemistry was used to detect the expression of E-cadherin and ß-catenin in colon tissues, and immunofluorescence was used to observe the infiltration of M2 macrophages in colon tissues. In cell experiments, we established a co-culture model of Fn and colon cancer cells and intervened with BXD-containing serum. Malignant behaviors such as cell proliferation, invasion, and migration were detected, as well as changes in their cell cycle. We examined the protein levels of E-cadherin, ß-catenin, Axin2, and Cyclin D1 in each group were detected by Western blot. We used US1 strain (fadA-) as a control and observed the effects of BXD-containing serum on Fn attachment and invasion of colon cancer cells through attachment and invasion experiments. RESULTS: BXD can inhibit the colitis-to-cancer transition in mice infected with Fn, reduce crypt structure damage, improve gut microbiota dysbiosis, upregulate E-cadherin and decrease ß-catenin expression, and reduce infiltration of M2 macrophages, thus inhibiting the process of colitis-to-cancer transition. Cell experiments revealed that BXD-containing serum can inhibit the proliferation, migration, and invasion of colon cancer cells infected with Fn and regulate their cell cycle. More importantly, we found that BXD-containing serum can inhibit the binding of Fn's FadA adhesin to E-cadherin, reduce Fn's attachment and invasion of colon cancer cells, thereby downregulating the E-cadherin/ß-catenin signaling pathway. CONCLUSIONS: These findings show that BXD can inhibit Fn colonization by interfering with the binding of FadA to E-cadherin, reducing the activation of the E-cadherin/ß-catenin signaling pathway, and ultimately delaying colitis-to-cancer transition.

Exposure to pesticides and risk of colorectal cancer: A systematic review and meta-analysis.

Colorectal cancer (CRC) is a widespread malignancy worldwide, and its relationship with pesticide exposure remains inconclusive. This study aims to elucidate the relationship between pesticide exposure and the risk of colon, rectal, or CRC, focusing on specific pesticide groups. We conducted an extensive literature search for peer-reviewed studies published up to March 31, 2023. Summary risk ratios (RR) and their corresponding 95% confidence intervals (CI) were calculated using stratified random-effects meta-analyses, taking into account different types of exposure and outcomes, and various exposed populations and pesticide subgroups. This approach aimed to address the substantial heterogeneity observed across the literature. We also assessed heterogeneity and potential small-study effects to ensure the robustness of our findings. From the 50 studies included in this review, 33 contributed to the meta-analysis. Our results indicate a significant association between herbicide exposure and colon cancer in both lifetime-days (LDs) (RR = 1.20; 95% CI = 1.01-1.42) and intensity-weighted lifetime-days (IWLDs) (RR = 1.29, 95% CI = 1.12-1.49) exposure. Similarly, insecticide exposure was associated with an increased risk of colon cancer in IWLDs (RR = 1.32; 95% CI = 1.02-1.70) exposure, and rectal cancer in any versus never exposure (RR = 1.21; 95% CI = 1.07-1.36), IDs (RR = 1.86; 95% CI = 1.30-2.67) and IWLDs (RR = 1.70; 95% CI = 1.03-2.83) exposure. While these findings suggest significant associations of herbicide and insecticide exposure with colon and rectal cancer, respectively, further research is needed to explore the impact of other pesticide groups and deepen our understanding of pesticide exposure. These results have important implications for policymakers and regulators, underscoring the need for stricter supervision and regulation of pesticide use to mitigate CRC risk.

Comparative Efficacy and Safety of Standard and Biweekly Trifluridine/Tipiracil Regimen in Patients With Colorectal Cancer.

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC. PATIENTS AND METHODS: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29). RESULTS: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999). CONCLUSION: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event.

Ripe papaya pectins inhibit the proliferation of colon cancer spheroids and the formation of chemically induced aberrant crypts in rats colons.

Pectins are a class of soluble polysaccharides that can have anticancer properties through several mechanisms. This study aimed to characterize the molecular structure of water-soluble fractions (WSF) derived from ripe and unripe papayas and assess their biological effects in two models: the 3D colon cancer spheroids to measure cell viability and cytotoxicity, and the in vivo model to investigate the inhibition of preneoplastic lesions in rats. WSF yield was slightly higher in ripe papaya, and both samples mainly consisted of pectin. Both pectins inhibited the growth of colon cancer HT29 and HCT116 spheroids. Unripe pectin disturbed HT29/NIH3T3 spheroid formation, decreased HCT116 spheroid viability, and increased spheroid cytotoxicity. Ripe pectin had a more substantial effect on the reduction of spheroid viability for HT29 spheroids. Furthermore, in vivo experiments on a rat model revealed a decrease in aberrant crypt foci (ACF) formation for both pectins and increased apoptosis in colonocytes for ripe papaya pectins. The results suggest potential anticancer properties of papaya pectin, with ripe pectin showing a higher potency.

Gastrointestinal perforation associated with bevacizumab in metastatic colorectal cancer.

OBJECTIVE: To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab. METHODS: We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation. RESULTS: All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. CONCLUSIONS: Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation.

Cadmium promotes the binding and centrosomal translocation of CCDC85C and PLK4 via ROS-GCLM pathway to trigger centrosome amplification in colon cancer cells.

Cadmium (Cd) is a prevalent heavy metal contaminant that can cause centrosome amplification (CA) and cancer. Since CA can initiate tumorigenesis, it is plausible that cadmium initiates tumorigenesis via CA. The present study investigated the signaling pathways underlying CA by Cd. Our findings confirmed that sub-toxic concentrations of Cd could induce CA in the HCT116 colon cancer cells, and revealed that reactive oxygen species (ROS), GCLM, CCDC85C and PLK4 were the signaling molecules that formed a pathway of ROS-GCLM-CCDC85C-PLK4. Cd not only increased the protein levels of CCDC85C and PLK4, but also promoted their distribution to the centrosomes. Molecular docking analysis revealed that CCDC85C and PLK4 had the binding potential. Indeed, antibodies against CCDC85C and PLK4 were able to pull down PLK4 and CCDC85C, respectively. Knockdown of CCDC85C decreased the Cd-promoted centrosomal distribution of PLK4. Similarly, knockdown of PLK4 reduced the centrosomal distribution of CCDC85C. Our results suggest that Cd activates ROS-GCLM pathway that triggers the expression of and binding between CCDC85C and PLK4, and promotes the translocation of CCDC85C-PLK4 complex to the centrosomes, which eventually leads to CA.

Anise (Pimpinella anisum L.) attenuates azoxymethane-induced colorectal cancer by antioxidant, anti-inflammatory, and anti-apoptotic pathways in rats.

Herbal medicine is one of the most common fields explored for combating colon cancers, and Pimpinella anisum L. seeds (PAS) have been utilized widely as medicinal agents because of their increased essential oil (trans-anethole) contents. In this essence, our study investigates the toxic effect and chemoprotective potentials of PAS against azoxymethane (AOM)-induced colon cancer in rats. The toxicity trial for PAS conducted by clustering fifteen rats into three groups (five rats each): A, normal control had 10% Tween 20; B, ingested with 2 g/kg PAS; and C, supplemented with 4 g/kg PAS. The in vivo cancer trial was performed by using 30 rats (Sprague-Dawley) that were randomly adapted in five steel cages (six rats each): group A, normal controls received two subcutaneous injections of normal saline 0.09% and ingested orally 10% Tween 20; groups B-E, rats received two injections of 15 mg/kg of azoxymethane (AOM) subcutaneously in 2 weeks and treated orally with 10% Tween 20 (group B) or intraperitoneal injection of 5-fluorouracil (35 mg/kg) (group C), or orally given 200 mg/kg PAS (group D) and 400 mg/kg PAS (group E) for 8 weeks. After the scarification of rats, the colon tissues were dissected for gross and histopathological evaluations. The acute toxicity trial showed the absence of any toxic signs in rats even after 14 days of ingesting 4 g/kg of PAS. The chemoprotective experiment revealed significant inhibitory potentials (65.93%) of PAS (400 mg/kg) against aberrant crypto foci incidence that could be correlated with its positive modulation of the immunohistochemically proteins represented by a significant up-regulation of the Bax protein and a decrease of the Bcl-2 protein expressions in colon tissues. Furthermore, PAS-treated rats had notably lower oxidative stress in colon tissues evidenced by decreased MDA levels and increased antiradical defense enzymes (SOD, CAT, and GPx). The outcomes suggest 400 mg/kg PAS as a viable additive for the development of potential pharmaceuticals against colorectal cancer.

[The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study].

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Inhibition of Acetylcholine Expression in the Tumor Microenvironment by Mustard Oil: A Potential Strategy to Retard Colon Cancer Progression.

Objective: This study aims to investigate the potential of mustard oil-induced reduction in acetylcholine expression as a means to delay the progression of colon cancer within the internal environment. Methods: The study design in this research involved both in vitro cellular experiments and in vivo animal experiments to employ mustard oil to modulate acetylcholine expression levels and evaluate its impact on colon cancer. Cellular experiments involved the introduction of six concentrations of acetylcholine (10-2, 10-3, 10-4, 10-5, 10-6, and 10-7 mol/L) into colon cancer cell cultures to monitor cell proliferation. Animal experiments encompassed the subcutaneous CT26 colon cancer cells implantation into 28 Balb/c mice, divided into experimental and control groups. After tumor establishment, both groups were fed standard diets for two weeks. Serum acetylcholine concentrations were measured from eye blood samples. Additionally, Balb/c mice were inoculated with CT26-derived colon cancer cells and further categorized into experimental and control groups. A total of 14 mice comprised each group, with experimental mice fed mustard oil and control mice fed soybean oil. Post two weeks, serum acetylcholine expression in both groups was assessed. After sacrifice, subcutaneous tumors were excised, and tumor dimensions were measured using a Vernier scale. Results: Acetylcholine concentration augmentation in the culture medium corresponded to gradual cell proliferation escalation, peaking at 10-5 mol/L, exhibiting statistical significance. Comparative analysis revealed significantly elevated relative acetylcholine expression levels in Balb/c mice with tumor-bearing colon cancers compared to normal Balb/c mice. Experimental group mice exhibited substantially lower serum acetylcholine concentrations than control group mice. Mustard oil administration effectively curtailed acetylcholine expression in normal Balb/c mice, consequently retarding tumor growth. These findings underscore mustard oil's potential to diminish serum acetylcholine expression, thereby delaying colon cancer progression. Conclusions: This study suggests that mustard oil's modulation of acetylcholine expression within the internal environment holds the potential for impeding colon cancer growth.

Panx1 knockout promotes preneoplastic aberrant crypt foci development in a chemically induced model of mouse colon carcinogenesis.

Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1-/- ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1-/- female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1-/- animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated.

Anticancer Effects of Washed-Dehydrated Solar Salt Doenjang on Colon Cancer-Induced C57BL/6 Mice.

This study researched the mineral composition of Korean washed-dehydrated solar salt (WDS) without bittern. It also evaluated the anticancer effects of doenjang (WDSD) prepared using WDS on azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer in C57BL/6 mice. The mineral composition of WDS showed lower Mg (11.71 ± 1.89 g/kg) and S (9.77 ± 2.88 g/kg) contents, and it was confirmed that mice in the WDSD group (AOM/DSS+WDSD) displayed significantly lower weight loss, colon length reduction, and tumor formation compared with the control (Con) group. In addition, pathologically, it was confirmed that the extent of epithelial cell damage and inflammation in the colon tissue of the WDSD group was restored to a state similar to that of the Nor group. Besides, WDSD regulated the protein expression of apoptosis (Bcl-2-associated X protein [Bax], B cell lymphoma-2 [Bcl-2], B cell lymphoma-extra large [Bcl-xL], and caspase 9, caspase 3), and p53, p21, and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α), thereby inducing the apoptosis and cell cycle arrest of cancer cells and suppressing inflammation. In addition, the intestinal microbiota of the mice treated with WDSD were more diverse, with an abundance of Bifidobacterium, a lactic acid bacterium beneficial to colon health, was also a greater presence of Faecalibaculum, which showed antitumor effects. These results indicate that solar salts and their different processing methods affect their functional health-promoting properties. In addition, the inhibitory effect on colon cancer was further enhanced when doenjang was prepared with WDS with low Mg and S content.

The Antiproliferative Activity of Adiantum pedatum Extract and/or Piceatannol in Phenylhydrazine-Induced Colon Cancer in Male Albino Rats: The miR-145 Expression of the PI-3K/Akt/p53 and Oct4/Sox2/Nanog Pathways.

Colon cancer is one of the most common types of cancer worldwide, and its incidence is increasing. Despite advances in medical science, the treatment of colon cancer still poses a significant challenge. This study aimed to investigate the potential protective effects of Adiantum pedatum (AP) extract and/or piceatannol on colon cancer induced via phenylhydrazine (PHZ) in terms of the antioxidant and apoptotic pathways and histopathologic changes in the colons of male albino rats. The rats were randomly divided into eight groups: control, AP extract, piceatannol (P), PHZ, PHZ and AP treatments, PHZ and P treatments, PHZ and both AP and P, and PHZ and prophylaxis with both AP and P. The results demonstrated that PHZ induced oxidative damage, apoptosis, and histopathological changes compared to the control group. However, the administration of AP or P or AP + P as therapy or prophylaxis significantly ameliorated these changes and upregulated the colonic mir-145 and mRNA expression of P53 and PDCD-4 while downregulating the colonic mRNA expression of PI3K, AKT, c-Myc, CK-20, SOX-2, OCT-4, and NanoG compared to the PHZ group. These findings suggest that the candidate drugs may exert their anti-cancer effects through multiple mechanisms, including antioxidant and apoptotic activities.

Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report.

Background: Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression. Main Body: This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse. Conclusions: Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.

Refined fiber inulin promotes inflammation-associated colon tumorigenesis by modulating microbial succinate production.

BACKGROUND AND AIM: There is an increased risk of colon cancer associated with inflammatory bowel disease (IBD). Dietary fibers (DFs) naturally present in vegetables and whole grains offer numerous beneficial effects on intestinal health. However, the effects of refined DFs on intestinal health remain unclear. Therefore, we elucidated the impact of the refined DF inulin on colonic inflammation and tumorigenesis. METHODS: Four-week-old wild-type (WT) mice were fed diets containing insoluble DF cellulose (control) or refined DF inulin for 4 weeks. A subgroup of mice was then switched to drinking water containing dextran sulfate sodium (DSS, 1.4% wt/vol) for colitis induction. In another subgroup of mice, colitis-associated colorectal cancer (CRC) was initiated with three 7-day alternate cycles of DSS following an initial dose of mutagenic substance azoxymethane (AOM; 7.5 mg/kg body weight; i.p.). Post 7 weeks of AOM treatment, mice were euthanized and examined for CRC development. RESULTS: Mice consuming inulin-containing diet exhibited severe colitis upon DSS administration, as evidenced by more body weight loss, rectal bleeding, and increased colonic inflammation than the DSS-treated control group. Correspondingly, histological analysis revealed extensive disruption of colon architecture and massive infiltration of immune cells in the inulin-fed group. We next examined the effect of inulin on CRC development. Surprisingly, significant mortality (~50%) was observed in the inulin-fed but not in the control group during the DSS cycle. Consequently, the remaining inulin-fed mice, which completed the study exhibited extensive colon tumorigenesis. Immunohistochemical characterization showed comparatively high expression of the cell proliferation marker Ki67 and activation of the Wnt signaling in tumor sections obtained from the inulin-fed group. Gut microbiota and metabolite analysis revealed expansion of succinate producers and elevated cecal succinate in inulin-fed mice. Human colorectal carcinoma cells (HCT116) proliferated more rapidly when supplemented with succinate in an inflamed environment, suggesting that elevated luminal succinate may contribute to tumorigenesis. CONCLUSIONS: Our study uncovers that supplementation of diet with refined inulin induces abnormal succinate accumulation in the intestinal lumen, which in part contributes to promoting colon inflammation and tumorigenesis.

Raptinal ameliorates 1,2-dimethylhydrazine-induced colon cancer through p53/Bcl2/Bax/caspase-3-mediated apoptotic events in vitro and in vivo.

OBJECTIVES: Colon carcinoma stands as the most familiar malignancy throughout across the globe. Raptinal induce apoptosis through the alteration of cellular events. Thus, in the present investigation, the anticancer activity of raptinal counter to 1,2-dimethylhydrazine (DMH) persuaded colon carcinoma has been evaluated through both in vivo and in vitro systems. MATERIALS AND METHODS: The pharmacophore analysis demonstrated the binding efficacy of raptinal with the apoptotic proteins. The chemotherapeutic activity of raptinal was examined through HT-29 human colorectal cancer (CRC) cell line as well as DMH persuaded CRC in the rat model. The cytotoxicity analysis, flow cytometry, and DAPI analysis have been carried out on HT-29 cell line through in vitro assessment. The colon carcinoma has been induced through DMH administration and subsequently Dextran sulfate sodium treatment in male Wistar rats. After 18 weeks of raptinal treatment, the colon tissues have been investigated for aberrant crypt foci (ACF) count, antioxidant status, histology, immunohistochemical assessment, and apoptotic analysis. RESULTS: The raptinal therapy on HT-29 cells demonstrated a substantial % of early apoptosis followed by G0 and G1 phase arrest, which subsequently led to apoptosis. Furthermore, it inhibits ACF development with improved colonic abrasions and structural integrity of colonic mucosa with increased levels of antioxidants, proapoptotic biomarkers including p53, caspase-3, Bax and downstream effects of Bcl-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 mutation. CONCLUSIONS: These findings indicate the raptinal effectively reduces colon cancer by inducing apoptosis through p53/Bcl2/Bax/caspase-3 pathway and suppressing IL-6, TNF-mediated chronic inflammation in the colon cancer microenvironment.

Geniposide prevents tumor growth by inhibiting colonic interleukin-1ß and monocyte chemoattractant protein-1 via down-regulated expression of cyclooxygenase-2 and thymocyte selection-associated high mobility box proteins TOX/TOX2 in azoxymethane/dextran sulfate sodium-treated mice.

Colon cancer was the second leading cause of cancer-related deaths in Japan in 2019. The effects of geniposide isolated from Gardenia jasminoides fructus (Rubiaceae) on the azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced growth of colon tumors and changes in interleukin (IL)-1 ß, monocyte chemoattractant protein (MCP)-1, IL-10, and programmed cell death-1 (PD-1) levels in the colon were investigated. The intraperitoneal administration of AOM (10 mg/kg) on days 0 and 27 induced colorectal carcinogenesis. Free access to 1% (w/v) DSS drinking water was given to mice on days 7-15, 32-33, and 35-38. Geniposide (30 and 100 mg/kg) was orally administered on days 1-16, discontinued for 11 days (days 16 to 26), and then administered again on days 27-41. Colonic levels of cytokines, chemokine, and PD-1 were measured using by enzyme-linked immunosorbent assay (ELISA). Increases in colorectal tumor numbers and areas were significantly inhibited by geniposide. In addition, geniposide (100 mg/kg) reduced colonic levels of IL-1 ß, MCP-1, PD-1 and IL-10 by 67.4, 57.2, 100%, and 100% respectively. Cyclooxygenase (COX)-2- and thymocyte selection high mobility group box proteins (TOX/TOX2)-positive cell numbers were significantly reduced by geniposide. Geniposide (30 and 100 mg/kg) decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) expressions in immunohistochemical analysis by 64.2 and 98.2%, respectively. Thus, the inhibitory effects of geniposide on colon tumor growth may be associated with reductions in the colonic levels of IL-1 ß, MCP-1, IL-10, and PD-1 via the down-regulated expression of COX-2 and TOX/TOX2 through the inhibition of Phospho-STAT3 expression (in vivo and in vitro).

Development of Pluoronic nanoparticles of fluorocoxib A for endoscopic fluorescence imaging of colonic adenomas.

Significance: Current white light colonoscopy suffers from many limitations that allow 22% to 32% of preneoplastic lesions to remain undetected. This high number of false negatives contributes to the appearance of interval malignancies, defined as neoplasms diagnosed between screening colonoscopies at a rate of 2% to 6%. Aim: The shortcomings of today's white light-based colorectal cancer screening are addressed by colonoscopic fluorescence imaging of preneoplastic lesions using targeted fluorescent agents to enhance contrast between the lesion and the surrounding normal colonic epithelium. Approach: We describe the development of Pluronic® nanoparticles of fluorocoxib A (FA), a fluorescent cyclooxygenase-2 (COX-2) inhibitor that enables targeted imaging of inflammation and cancer in numerous animal models, for endoscopic florescence imaging of colonic adenomas. Results: We formulated FA, a fluorescent COX-2 inhibitor, or fluorocoxib negative control (FNC), a nontargeted fluorophore and a negative control for FA, in micellar nanoparticles of FDA approved Pluronic tri-block co-polymer using a bulk solvent evaporation method. This afforded FA-loaded micellar nanoparticles (FA-NPs) or FNC-loaded micellar nanoparticles (FNC-NPs) with the hydrodynamic diameters ( D h ) of 45.7 ± 2.5 nm and 44.9 ± 3.8 nm and the zeta potentials ( ζ ) of - 1.47 ± 0.3 mV and - 1.64 ± 0.5 mV , respectively. We intravenously injected B6;129 mice bearing colonic adenomas induced by azoxymethane and dextran-sodium sulfate with FA-loaded Pluronic nanoparticles (FA-NPs). The diffusion-mediated local FA release and its binding to COX-2 enzyme allowed for clear detection of adenomas with high signal-to-noise ratios. The COX-2 targeted delivery and tumor retention were validated by negligible tumor fluorescence detected upon colonoscopic imaging of adenoma-bearing mice injected with Pluronic nanoparticles of FNC or of animals predosed with the COX-2 inhibitor, celecoxib, followed by intravenous dosing of FA-NPs. Conclusions: These results demonstrate that the formulation of FA in Pluronic nanoparticles overcomes a significant hurdle to its clinical development for early detection of colorectal neoplasms by fluorescence endoscopy.

Combining gamma-tocopherol and aspirin synergistically suppresses colitis-associated colon tumorigenesis and modulates the gut microbiota in mice, and inhibits the growth of human colon cancer cells.

Despite being shown to be effective for chemoprevention of colorectal cancer, aspirin has limitations including adverse effects and inability to block colitis-associated colon cancer (CAC). γ-Tocopherol (γT), a vitamin E form, has been reported to mitigate experimental colitis and CAC, prolong the anti-inflammatory activity of aspirin and alleviate aspirin-induced adverse effect. We therefore hypothesize that combining γT and aspirin is better than either compound singly for suppressing CAC. This hypothesis was tested in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model and with human HCT116 colon cancer cells. Compared to the control, combining aspirin (250 ppm) and γT (500 ppm) but not either compound alone significantly reduced AOM/DSS-induced tumor area and multiplicity of large-size tumors by 60% and 50%, respectively. Meanwhile, γT mitigated aspirin-promoted inflammation and stomach lesions in mice. Moreover, the combination appeared to cause favorable changes of gut microbiota compared to the control and synergistically suppressed the growth of HCT116 cells. Our study demonstrates that combining aspirin and γT improves anticancer effects and counteracts side effects compared to aspirin and may therefore be a novel combinatory chemopreventive agent against CAC.

Acertannin prevents azoxymethane/dextran sulfate sodium-induced colon cancer growth by inhibiting the colonic expression of interleukin-1ß, monocyte chemoattractant protein-1, cyclooxygenase-2, and thymocyte selection-associated high mobility group box proteins (TOX)/TOX2 in C57BL/6J mice.

Colon cancer was the second leading cause of cancer-related death in 2019. We herein investigated the effects of acertannin containing Acer species on azoxymethane (AOM)/dextran sulfate sodium (DDS)-induced colon cancer growth and changes in the colonic levels of interleukin (IL)-1ß, monocyte chemoattractant protein (MCP)-1, IL-10, and programmed cell death-1 (PD-1). Colorectal carcinogenesis was induced by an intraperitoneal injection of AOM (10 mg/kg) on days 0 and 27. Mice were given 1% (w/v) DSS drinking water ad libitum on days 7-14, 32-33, and 35-38. Acertannin (30 and 100 mg/kg) was orally administered on days 1-16, discontinued for 11 days (days 16-26), and then administered again on days 27-41. The colonic levels of cytokines, a chemokine, and PD-1 were measured using the respective ELISA kits. The number and area of tumors in mice treated with acertannin (100 mg/kg) decreased by 53.9 and 63.1%, respectively. Furthermore, the colonic levels of IL-1ß, MCP-1, IL-10, and PD-1 showed reductions of 57.3, 62.9, 62.8, and 100%, respectively, while the numbers of cyclooxygenase-2 (COX-2)-, thymocyte selection-associated high mobility group box proteins (TOX)/TOX2-, PD-1-, and signal transducer and activator of transcription 3 (STAT3) phosphorylation-positive numbers decreased by 79.6, 77.9, 93.8, and 100%, respectively. In conclusion, the inhibitory effects of acertannin on AOM/DSS-induced colon tumor growth appear to be associated with reductions in the colonic levels of IL-1ß, MCP-1, IL-10, and PD-1 through the down-regulated expression of COX-2 and TOX/TOX2 in the tumor microenvironment.