Treatment Of Colorectal Cancer Research Articles

The Role and Therapeutic Potential of Pyroptosis in Colorectal Cancer: A Review.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC.

Therapeutic and diagnostic applications of exosomes in colorectal cancer.

Exosomes play a key role in colorectal cancer (CRC) related processes. This review explores the various functions of exosomes in CRC and their potential as diagnostic markers, therapeutic targets, and drug delivery vehicles. Exosomal long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) significantly influence CRC progression. Specific exosomal lncRNAs are linked to drug resistance and tumor growth, respectively, highlighting their therapeutic potential. Similarly, miRNAs like miR-21, miR-10b, and miR-92a-3p, carried by exosomes, contribute to chemotherapy resistance by altering signaling pathways and gene expression in CRC cells. The review also discusses exosomes' utility in CRC diagnosis. Exosomes from cancer cells have distinct molecular signatures compared to healthy cells, making them reliable biomarkers. Specific exosomal lncRNAs (e.g., CRNDE-h) and miRNAs (e.g., miR-17-92a) have shown effectiveness in early CRC detection and monitoring of treatment responses. Furthermore, exosomes show promise as vehicles for targeted drug delivery. The potential of mesenchymal stem cell (MSC)-derived exosomes in CRC treatment is also noted, with their role varying from promoting to inhibiting tumor progression. The application of multi-omics approaches to exosome research is highlighted, emphasizing the potential for discovering novel CRC biomarkers through comprehensive genomic, transcriptomic, proteomic, and metabolomic analyses. The review also explores the emerging field of exosome-based vaccines, which utilize exosomes' natural properties to elicit strong immune responses. In conclusion, exosomes represent a promising frontier in CRC research, offering new avenues for diagnosis, treatment, and prevention. Their unique properties and versatile functions underscore the need for continued investigation into their clinical applications and underlying mechanisms.

Genetic drivers for inflammatory protein markers in colorectal cancer: a Mendelian randomization approach to clinical prognosis study

To explore the causal relationship between inflammatory protein markers and the risk of colorectal cancer using a Mendelian randomization (MR) approach. We obtained data pertaining to colorectal cancer from Genome-Wide Association Study (GWAS) datasets and used 91 inflammatory protein markers as the exposure variables. A two-sample MR analysis model was used to assess the causal link between the inflammatory markers and colorectal cancer risk. The robustness of the results was evaluated through heterogeneity, pleiotropy, and sensitivity analyses using 5 MR models: Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Simple Mode, and Weighted Mode. We examined the mRNA expressions of PD-L1, AXIN1, and β-NGF using RT-qPCR in 86 untreated patients with colorectal adenocarcinoma admitted in Nanfang Hospital between December, 2021 and December 2023, and analyzed their correlation with the clinical characteristics of the patients. Using the IVW model, MR analysis revealed significant causal associations between a reduced risk of colorectal cancer and lowered expressions of AXIN1 (OR=0.866, 95% CI: 0.754-0.994, P=0.040), β-NGF (OR=0.914, 95% CI: 0.843-0.990, P=0.028; OR=0.884, 95% CI: 0.784-0.998, P=0.047 using Weighted Median model), and PD-L1 (OR=0.903, 95% CI: 0.824- 0.989, P=0.028). No significant heterogeneity or pleiotropy was observed, indicating good stability of the results. Sensitivity analysis confirmed the reliability of the findings. The clinical study demonstrated a significant correlation between PD-L1 expression and TNM staging, particularly in stage Ⅳ patients (P=0.007). AXIN1 and β -NGF expression levels were significantly correlated with the degree of tumor differentiation, and their expressions were higher in poorly differentiated samples (P<0.001). Lowered expressions of inflammatory protein markers AXIN1, β-NGF, and PD-L1 are causally correlated with a reduced risk of colorectal cancer and their expression levels are associated with TNM staging and tumor differentiation. These markers may thus serve as potential targets for colorectal cancer treatment and prevention.

Activation of p38 and JNK by ROS Contributes to Deoxybouvardin-Mediated Intrinsic Apoptosis in Oxaliplatin-Sensitive and -Resistant Colorectal Cancer Cells.

Colorectal cancer (CRC) remains a global health burden, accounting for almost a million deaths annually. Deoxybouvardin (DB), a non-ribosomal peptide originally isolated from Bouvardia ternifolia, has been reported to possess antitumor activity; however, the detailed mechanisms underlying this anticancer activity have not been elucidated. We investigated the anticancer activity of the cyclic hexapeptide, DB, in human CRC HCT116 cells. Cell viability, evaluated by MTT assay, revealed that DB suppressed the growth of both oxaliplatin (Ox)-resistant HCT116 cells (HCT116-OxR) and Ox-sensitive cells in a concentration- and time-dependent manner. Increased reactive oxygen species (ROS) generation was observed in DB-treated CRC cells, and it induced cell cycle arrest at the G2/M phase by regulating p21, p27, cyclin B1, and cdc2 levels. In addition, Western blot analysis revealed that DB activated the phosphorylation of JNK and p38 MAPK in CRC. Furthermore, mitochondrial membrane potential (MMP) was dysregulated by DB, resulting in cytochrome c release and activation of caspases. Taken together, DB exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, increasing cellular ROS levels, and disrupting MMP. Thus, DB is a potential therapeutic agent for the treatment of Ox-resistant CRC.

Identification of ASMTL-AS1 and LINC02604 lncRNAs as novel biomarkers for diagnosis of colorectal cancer

PurposeColorectal cancer is one of the major leading causes of death worldwide, and available treatments for advanced colorectal cancer are not successful. Therefore, early detection of colorectal cancer is essential to improve patient survival, and biomarkers are potential tools to achieve this goal. Considering the key role of lncRNAs in cancers, the aim of this study is to identify lncRNAs involved in colorectal cancer as new potential prognosis biomarkers for CRC.MethodsIn this observational study, gene expression data obtained from the TCGA database were analyzed, Identification of differentially expressed mRNAs, miRNAs, and lncRNAs was performed, and ceRNA network was drawn. Also, survival analysis of patients was performed in order to identify potential biomarkers related to the diagnosis and prognosis of colon cancer. After confirming the results using the GSE39582 dataset, the expression of target lncRNAs in colorectal tumor tissues was also investigated to confirm the bioinformatic data.ResultsAnalysis of the TCGA data showed that the expression of three lncRNAs—SNHG7, ASMTL-AS1, and LINC02604—that had the highest interaction with other miRNAs and mRNAs identified based on the ceRNA network was increased in colorectal cancer. Also, based on the ceRNA network, three microRNAs, hsa-let-7d-5p, hsa-mir-92a-3p, and hsa-mir-423-5p, and eight mRNAs, including CPA4, MSI2, RRM2, IGF2BP1, ONECUT2, HMGA1, SOX4, and SRM, were associated with all three mentioned lncRNAs, the expression of microRNAs was decreased and the expression of mRNAs was increased. By enrichment analysis, it was found that the target lncRNAs are involved in the processes of cell proliferation, apoptosis, and metastasis, indicating their importance in the development and malignancy of colorectal cancer. Furthermore, Kaplan–Meier analysis showed a significant increase in mortality in patients with higher expression levels of these lncRNAs. Analysis of the GSE39582 dataset, and real-time RT-PCR analysis, confirmed our bioinformatic results. Also, ROC analysis showed that SNHG7 was a relatively good promising biomarker (AUC = 0.73, p value = 0.02), while ASMTL-AS1 (AUC = 0.92, p value < 0.0001) and LINC02604 (AUC = 1.00, p value < 0.0001) emerged as excellent diagnostic biomarkers in colorectal cancer.ConclusionIt seems that increased expression of lncRNAs ASMTL-AS1 and LINC02604 can serve as molecular biomarkers for CRC, possibly through the sponge hsa-let-7d-5p, hsa-mir-92a-3p, and hsa-mir-423 5p, which increases target mRNAs, which are effective in the carcinogenesis process.

Long noncoding RNA KCNMA1-AS2 regulates the function of colorectal cancer cells and sponges miR-1227-5p

BackgroundMany long noncoding RNAs (lncRNAs) with altered expression significantly influence colorectal cancer (CRC) progression and behavior. The functions of many lncRNAs in CRC are not clear yet. This study aimed to discover novel lncRNA entities and comprehensively examine and validate their roles and underlying molecular mechanisms in CRC.MethodsTissue samples, both tumourous and non-tumourous, from three CRC patients were submitted for sequencing. Following expression validation in samples from ten patients and four CRC cell lines. The lncRNA KCNMA1-AS2 was synthesized by In-vitro transcription RNA synthesis and the lncRNA was directly transfected into CRC cell lines to overexpress. Functional assays including MTT proliferation assay, Annexin-V/propidium iodide apoptosis assay, wound healing migration assay and cell cycle assays were performed to evaluate the effect of overexpression of KCNMA1-AS2. Furthermore, the binding of KCNMA1-AS2 to miR-1227-5p was confirmed using dual luciferase reporter assays and qPCR analyses. Subsequent bioinformatics analyses identified 58 potential downstream targets of miR-1227-5p across three databases.ResultsIn this study, we identified the lncRNA KCNMA1-AS2, the expression of which was down-regulated consistently in cancer tissues and CRC cell lines compared to non-cancerous tissues. The overexpression of lncRNA KCNMA1-AS2 led to significant reduction in CRC cell proliferation and migration, increase in cell apoptosis, and more cells arrested in S phase. Additionally, the interaction between KCNMA1-AS2 and miR-1227-5p was confirmed through dual luciferase reporter assay and qPCR analysis. It is also putatively predicted that MTHFR and ST8SIA2 may be linked to CRC based on bioinformatics analyses.ConclusionsLncRNA KCNMA1-AS2 exhibited distinct gene expression patterns in both CRC tissue and cell lines, impacting various cellular functions while also acting as a sponge for miR-1227-5p.The findings spotlight lncRNA KCNMA1-AS2 as a potential marker for diagnosis and treatment of CRC.

Research progress on the correlation between intestinal flora and colorectal cancer.

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies in the world. With the rapid pace of life and changes in diet structure, the incidence and mortality of CRC increase year by year posing a serious threat to human health. As the most complex and largest microecosystem in the human body, intestinal microecology is closely related to CRC. It is an important factor that affects and participates in the occurrence and development of CRC. Advances in next-generation sequencing technology and metagenomics have provided new insights into the ecology of gut microbes. It also helps to link intestinal flora with CRC, and the relationship between intestinal flora and CRC can be continuously understood from different levels. This paper summarizes the relationship between intestinal flora and CRC and its potential role in the diagnosis of CRC providing evidence for early screening and treatment of CRC.

Circ_0000395 promotes cell growth, metastasis and oxaliplatin resistance by regulating miR-153–5p/MYO6 in colorectal cancer

BackgroundCircular RNAs (circRNAs) are involved in the regulation of colorectal cancer (CRC) progression and chemoresistence. Here, we attempted to reveal the function and mechanism of circ_0000395 in CRC chemoresistence. MethodsThe expression levels of circ_0000395, microRNA (miR)-153–5p, and myosin VI (MYO6) were determined by quantitative real-time PCR. Cell growth, metastasis and oxaliplatin resistance were evaluated via EdU assay, colony formation assay, flow cytometry, transwell assay, and cell counting kit 8 assay. Xenograft tumor model was adopted to evaluate the role of circ_0000395 on CRC tumor growth and oxaliplatin sensitivity. Protein expression of drug-resistance markers and MYO6 was analyzed by western blot. The target relationship between miR-153–5p and circ_0000395 or MYO6 was validated via dual-luciferase reporter assay and RIP assay. ResultsCirc_0000395 expression was enhanced in CRC tissues and cells. Silencing of circ_0000395 repressed CRC cell proliferation, migration and invasion, while promoted apoptosis and oxaliplatin sensitivity. Besides, circ_0000395 knockdown also reduced CRC tumor growth and enhanced the sensitivity of tumor to oxaliplatin. Additionally, circ_0000395 acted as a sponge for miR-153–5p, and miR-153–5p targeted MYO6. Functional experiments suggested that miR-153–5p inhibitor or MYO6 overexpression could reverse the suppressive effect of circ_0000395 knockdown on CRC cell growth, metastasis and oxaliplatin resistance. ConclusionCirc_0000395 promoted CRC cell growth, metastasis and oxaliplatin resistance via the miR-153–5p/MYO6 axis, which might provide new insights into the treatment of CRC.

Erlotinib Treatment in Colorectal Cancer Suppresses Autophagy Based on KRAS Mutation.

The KRAS gene is mutated in approximately 45% of colorectal cancer patients. There are currently very few targeted treatments or therapies equipped to directly inhibit KRAS due to its unusual structural intricacies. Erlotinib, an EGFR inhibitor, has previously been demonstrated to reduce cell viability by inducing autophagy in lung cancer cell lines with varying EGFR mutations. In contrast to lung cancer cells, evidence is provided herein for the first time that erlotinib treatment in colorectal cancer (CRC) cell lines reduces autophagy and still results in decreased cell viability. However, the effects of erlotinib in CRC cell lines containing a wildtype KRAS gene were different than in cells carrying a mutant KRAS gene. We show that there is significantly more downregulation of autophagy in KRAS mutant CRC cells compared to KRAS wildtype cells, both at transcriptional and translational levels, suggesting that the KRAS mutation is advantageous for cancer growth, even in the presence of erlotinib. Cell viability results determined that KRAS wildtype CRC cells had significantly more cell death compared to KRAS mutant cells. Using patient mRNA datasets, we showed that there was a significant correlation between the presence of the KRAS mutation and the expression of autophagy proteins. Additionally, through molecular dynamics simulations, we develop a blueprint for KRAS and autophagy protein interaction and the impact of the KRAS mutation on autophagy protein regulation. Overall, this is the first report of erlotinib treatment in CRC cells that assesses autophagy, and we demonstrate that autophagy activity is downregulated in these cells. This effect is not only greater in cells carrying a KRAS mutation compared to wildtype cells, but the KRAS mutant cells also have increased cell viability compared to wildtype cells. We hypothesize that the difference in cell viability and autophagy expression between KRAS mutant and KRAS wildtype cells after treatment with erlotinib can be of therapeutic value to treat CRC patients carrying KRAS mutations.

Subacute inferior vena cava occlusion after treatment for advanced colorectal cancer: presentation and management

Thrombosis of the inferior vena cava is an uncommon condition and may not be recognized until the affected patient develops severe symptoms. It is associated with a higher risk of complications than other locations of deep venous thrombosis. Here we present a case of a 72-year-old man with bilateral occlusion of the external iliac veins and inferior vena cava. Keywords: Inferior vena cava, thrombosis, managemen

RBM5 suppresses proliferation, metastasis and glycolysis of colorectal cancer cells via stabilizing phosphatase and tensin homolog mRNA.

RNA binding motif 5 (RBM5) has emerged as crucial regulators in many cancers. To explore more functional and mechanistic exploration of RBM5 since the lack of research on RBM5 in colorectal cancer (CRC) dictates that is essential. Through Gene Expression Profiling Interactive Analysis, we analyzed RBM5 expression in colon adenocarcinoma and rectum adenocarcinoma tissues. For detecting the mRNA expression of RBM5, quantitative real time-polymerase chain reaction was performed. Protein expression levels of RBM5, hexokinase 2, lactate dehydrogenase A, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), and AKT were determined via Western blot. Functionally, cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EDU) assay were performed to evaluate proliferation of CRC cells. Invasiveness and migration of CRC cells were evaluated through conducting transwell assays. Glucose consumption, lactate production and adenosine-triphosphate (ATP) production were measured through a glucose assay kit, a lactate assay kit and an ATP production assay kit, respectively. Besides, RNA immunoprecipitation assay, half-life RT-PCR and dual-luciferase reporter assay were applied to detect interaction between RBM5 and PTEN. To establish a xenotypic tumor mice, CRC cells were subcutaneously injected into the right flank of each mouse. Protein expression of RBM5, Ki67, and PTEN in tumor tissues was examined using immunohistochemistry staining. Haematoxylin and eosin staining was used to evaluate tumor liver metastasis in mice. We discovered down-regulation of RBM5 expression in CRC tissues and cells. RBM5 overexpression repressed proliferation, migration and invasion of CRC cells. Meantime, RBM5 impaired glycolysis in CRC cells, presenting as decreased glucose consumption, decreased lactate production and decreased ATP production. Besides, RBM5 bound to PTEN mRNA to stabilize its expression. PTEN expression was positively regulated by RBM5 in CRC cells. The protein levels of PI3K and p-AKT were significantly decreased after RBM5 overexpression. The suppressive influences of RBM5 on glycolysis, proliferation and metastasis of CRC cells were partially counteracted by PTEN knockdown. RBM5 suppressed tumor growth and liver metastasis in vivo. This investigation provided new evidence that RBM5 was involved in CRC by binding to PTEN, expanding the importance of RBM5 in the treatment of CRC.

Development and biological evaluation of 68Ga-labeled peptides for potential application in HER2-positive colorectal cancer

Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world. Human epidermal growth factor receptor 2 (HER2) is a promising target for the diagnosis and treatment of CRC. In this study, we aimed to design, synthesize and label peptide-based positron emission tomography (PET) tracers targeting HER2-positive CRC, namely [68Ga]Ga-ES-01 and [68Ga]Ga-ES-02. The results show that [68Ga]Ga-ES-01 and [68Ga]Ga-ES-02 possessed hydrophilicity, rapid pharmacokinetic properties and excellent stabilities. [68Ga]Ga-ES-02 demonstrated higher binding affinity (Kd = 24.29 ± 4.95 nM) toward the HER2 in CRC. In HER2-positive HT-29 CRC xenograft mouse model, PET study showed specific tumor uptake after injection of [68Ga]Ga-ES-02 (SUV15min max = 0.87 ± 0.03; SUV30min max = 0.64 ± 0.02). In biodistribution study, the T/M ratios of 68Ga-ES-02 at 30 min after injection reached a maximum of 4.07 ± 0.34. In summary, we successfully synthesized and evaluated two novel peptide-based PET tracers. Our data demonstrate that [68Ga]Ga-ES-01/02 is capable of HER2-positive colorectal cancer, with [68Ga]Ga-ES-02 showing superior imaging effect, enhanced targeting, and increased specificity.

Disparities in the diagnosis and treatment of colorectal cancer among patients with disabilities.

Little is known about disparities in diagnosis and treatment among colorectal cancer (CRC) patients with and without disabilities. To investigate the patterns of diagnosis, treatment, and survival for people with and without disabilities who had CRC. We performed a retrospective analysis using the Korean National Health Insurance Service database, disability registration data, and Korean Central Cancer Registry data. The analysis included 21449 patients with disabilities who were diagnosed with CRC and 86492 control patients diagnosed with CRC. The overall distribution of CRC stage was not affected by disability status. Subjects with disabilities were less likely than those without disabilities to undergo surgery [adjusted odds ratio (aOR): 0.85; 95% confidence interval (95%CI): 0.82-0.88], chemotherapy (aOR: 0.84; 95%CI: 0.81-0.87), or radiotherapy (aOR: 0.90; 95%CI: 0.84-0.95). The rate of no treatment was higher in patients with disabilities than in those without disabilities (aOR: 1.48; 95%CI: 1.41-1.55). The overall mortality rate was higher in patients with disabilities [adjusted hazard ratio (aHR): 1.24; 95%CI: 1.22-1.28], particularly severe disabilities (aHR: 1.57; 95%CI: 1.51-1.63), than in those without disabilities. Patients with severe disabilities tended to have a late or unknown diagnosis. Patients with CRC and disabilities had lower rates of treatment with almost all modalities compared with those without disabilities. During the follow-up period, the mortality rate was higher in patients with disabilities than in those without disabilities. The diagnosis and treatment of CRC need improvement in patients with disabilities.

Anthocyanin-Rich Berry Extracts Affect SN-38-Induced Response: A Comparison of Non-Tumorigenic HCEC-1CT and HCT116 Colon Carcinoma Cells.

Chemotherapy with irinotecan (CPT-11), the pro-drug of the highly cytotoxic SN-38, is among the standard-of-care treatments for colorectal cancer. To counteract undesired toxic side effects on healthy tissue such as the intestinal epithelium, the use of preparations rich in polyphenols with anti-oxidative and anti-inflammatory properties such as anthocyanins has been proposed. In the present study, the question of whether non-tumorigenic human epithelium cells (HCEC-1CT) can be protected against the cytotoxic impact of SN-38 by anthocyanin-rich polyphenol extracts without compromising the desired therapeutic effect against tumor cells (HCT-116) was addressed. Hence, single and combinatory effects of anthocyanin-rich polyphenol extracts of elderberry (EB), bilberry (Bil), blackberry (BB) and black currant (BC) with the chemotherapeutic drug SN-38 were investigated. Out of the extracts, BB showed the most potent concentration-dependent cytotoxicity alone and in combination with SN-38, with even stronger effects in non-tumorigenic HCEC-1CT cells. In cytotoxic concentrations, BB decreased the level of DNA/topoisomerase I covalent complexes in HCEC-1CT cells below base level but without concomitant reduction in SN-38-induced DNA strand breaks. The herein reported data argue towards an interference of anthocyanins with successful treatment of cancer cells and a lack of protective properties in healthy cells.

Translational Pharmacokinetic-Toxicodynamic Model of Myelosuppression for Dose Optimization in Combination Chemotherapy of Capecitabine and Oxaliplatin from Rats to Humans.

XELOX therapy, which comprises capecitabine and oxaliplatin, is the standard first-line chemotherapeutic regimen for colorectal cancer. However, its myelosuppressive effects pose challenges for its clinical management. Mathematical modeling combining pharmacokinetics (PK) and toxicodynamics (TD) is a promising approach for optimizing dosing strategies and reducing toxicity. This study aimed to develop a translational PK-TD model using rat data to inform dosing strategies and TD implications in humans. The rats were administered capecitabine, oxaliplatin, or XELOX combination regimen, and PK and TD data were collected. PK parameters were analyzed using sequential compartment analysis, whereas TD responses were assessed using Friberg's semiphysiological model. A toxicity intensity-based nomogram recommends optimal dosing strategies. Translational modeling techniques using the hybrid PK-TD model were employed to predict clinical responses. The PK-TD model successfully predicted the time-course profiles of hematological responses in rats following monotherapy and XELOX combination treatment. Interactive effects on lymphocytopenia were identified with the coadministration of capecitabine and oxaliplatin. A model-based recommended combination of the dose reduction rate for escaping severe lymphocytopenia was proposed as 40% and 60% doses of capecitabine and oxaliplatin, respectively. The current translational model techniques successfully simulated the time-course profiles of blood cell counts with confidence intervals in patients using rat data. Our study provides valuable insights into dose optimization strategies for each individual drug within the XELOX regimen and underscores the potential of translational modeling to improve patient outcomes. In addition to dose determination, these data will lay the groundwork for advancing drug development processes in oncology. SIGNIFICANCE STATEMENT: This study introduced a novel translational modeling approach rooted in a rat PK-TD model to optimize dosing strategies for the XELOX regimen for colorectal cancer treatment. Our findings highlight the interactive effects on lymphocytopenia and suggest a toxicity intensity-based nomogram for dose reduction, thus advancing precision medicine. This translational modeling paradigm enhances our understanding of drug interactions, offering a tool to tailor dosing, minimize hematological toxicity, and improve therapeutic outcomes in patients undergoing XELOX therapy.

Integrating UHPLC-Q-TOF-MS/MS, network pharmacology, bioinformatics and experimental validation to uncover the anti-cancer mechanisms of TiaoPi AnChang decoction in colorectal cancer

Ethnopharmacological relevanceThe TiaoPi AnChang Decoction (TPACD), a Traditional Chinese Medicine (TCM) prescription based on Xiangsha Liujunzi Decoction, has demonstrated clinical efficacy as an adjuvant therapy for colorectal cancer (CRC) patients. However, its specific ingredients and potential mechanisms of action remain unclear. Aim of the studyTo identify the primary active ingredients of TPACD, their molecular targets, and potential mechanisms underlying the efficacy of TPACD in CRC treatment. Materials and methodsThis study investigated the clinically validated TCM formula TPACD. In vitro and in vivo experiments were used to demonstrate TPACD's regulatory effects on various malignant phenotypes of tumors, providing basic research support for its anti-cancer activity. To understand its pharmacodynamic basis, we utilized ultra-high performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry/mass spectrometry (UHPLC-Q-TOF-MS/MS) to analyze TPACD constituents present in the bloodstream. Network pharmacology and bioinformatics analyses were used to identify potential active components and their molecular targets for TPACD's therapeutic effects in CRC. Subsequent experiments further elucidated its pharmacological mechanism. ResultsTPACD inhibits various malignant cellular processes, such as cell proliferation, apoptosis, migration, and invasion, and has shown potential anti-CRC activities both in vitro and in vivo. Following the identification of 109 constituents absorbed into the blood from TPACD, network pharmacology analysis predicted 42 potential anti-CRC targets. Clinical analyses highlighted three genes as prognostic key genes of TPACD's therapeutic action: C-X-C motif chemokine ligand 8 (CXCL8), fatty acid binding protein 4 (FABP4), and matrix metallopeptidase 3 (MMP3). Drug sensitivity analyses, molecular docking simulations and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) identified MMP3 as the most promising target for TPACD's anti-CRC action. Enzyme activity assays confirmed that TPACD inhibits MMP3 enzyme activity. Surface plasmon resonance (SPR) characterized the binding affinity between MMP3 and effective active components of TPACD, including luteolin, quercetin, kaempferol, and liensinine. ConclusionsTPACD exhibits anti-CRC activity in vitro and in vivo, with MMP3 identified as a critical target. The active compounds, including luteolin, quercetin, kaempferol, and liensinine, absorbed into the bloodstream, contribute to TPACD's efficacy by targeting MMP3.

Clinical features associated with NeoRAS wild-type metastatic colorectal cancer A SCRUM-Japan GOZILA substudy

“NeoRAS WT” refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible. NeoRAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. NeoRAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B. Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with NeoRAS WT emergence. Overall, 1/6 and 2/6 patients with NeoRAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively. NeoRAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective.

Innovations in colorectal cancer treatment: trifluridine and tipiracil with bevacizumab for improved outcomes - a review.

Colorectal cancer ranks second in cancer-related deaths throughout the world. At the time of diagnosis, at least 20% of the patients with CRC had already developed metastases. Treating and effectively managing metastatic colorectal cancer remains an unsolved task for the health sector. Research and clinical trials have been done to find the best possible solution for patients diagnosed with metastatic colorectal cancer. The approval of the combination therapy of trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) is a remarkable breakthrough in CRC treatment. Our goal through this article is to give detailed knowledge about the pathogenesis of CRC, its prevalence, and its clinical features. Here, we have also discussed the past medical treatments that have been used for treating mCRC, including the anti-EGFR therapy, aflibercept, ramucirumab, and regorafenib. However, the focus of this document is to assess the combination of LONSURF (trifluridine/tipiracil) and bevacizumab by reviewing the clinical trials and relevant research.

Curcumin-shellac nanoparticle-loaded GelMA/SilMA hydrogel for colorectal cancer therapy

In this study, a novel approach was employed to develop a therapeutic system for colorectal cancer treatment. Specifically, a GelMA/SilMA hydrogel loaded with curcumin-shellac nanoparticles (Cur@Lac NPs) was created. A microfluidic swirl mixer was utilized to formulate stable Cur@Lac NPs, ensuring their consistent and effective encapsulation. The pH-specific release of curcumin from the NPs demonstrated their potential for colon cancer treatment. By carefully regulating the ratio of GelMA (gelatin methacrylate) and SilMA (silk fibroin methacrylate), a GelMA/SilMA dual network hydrogel was generated, offering controlled release and degradation capabilities. The incorporation of SilMA notably enhanced the mechanical properties of the dual network matrix, improving compression resistance and mitigating deformation. This mechanical improvement is crucial for maintaining the structural integrity of the hydrogel during in vivo applications. In comparison to the direct incubation of curcumin, the strategy of encapsulating curcumin into NPs and embedding them within the GelMA/SilMA hydrogel resulted in more controlled release mechanisms. This controlled release was achieved through the disintegration of the NPs and the swelling and degradation of the hydrogel matrix. The encapsulating strategy also demonstrated enhanced cellular uptake of curcumin, leveraging the advantages of both NPs and in-situ hydrogel injection. This combination ensures a more efficient and sustained delivery of the therapeutic agent directly to the tumor site. Overall, this approach holds significant promise as a smart drug delivery system, potentially improving the efficacy of colorectal cancer treatments by providing targeted, controlled, and sustained drug release with enhanced mechanical stability and biocompatibility.

Use of automated assessment for determining associations of low muscle mass and muscle loss with overall survival in patients with colorectal cancer – A validation study

BackgroundLow muscle mass and skeletal muscle mass (SMM) loss are associated with adverse patient outcomes, but the time-consuming nature of manual SMM quantification prohibits implementation of this metric in clinical practice. Therefore, we assessed the feasibility of automated SMM quantification compared to manual quantification. We evaluated both diagnostic accuracy for low muscle mass and associations of SMM (change) with survival in colorectal cancer (CRC) patients. MethodsComputed tomography (CT) images from CRC patients enrolled in two clinical studies were analyzed. We compared i) manual vs. automated segmentation of preselected slices at the third lumbar [L3] vertebra ("semi-automated"), and ii) manual L3-slice-selection + manual segmentation vs. automated L3-slice-selection + automated segmentation ("fully-automated"). Automated L3-selection and automated segmentation was performed with Quantib Body Composition v0.2.1. Bland-Altman analyses, within-subject coefficients of variation (WSCVs) and Intraclass Correlation Coefficients (ICCs) were used to evaluate the agreement between manual and automatic segmentation. Diagnostic accuracy for low muscle mass (defined by an established sarcopenia cut-off) was calculated with manual assessment as the “gold standard”. Using either manual or automated assessment, Cox proportional hazard ratios (HRs) were used to study the association between changes in SMM (>5% decrease yes/no) during first-line metastatic CRC treatment and mortality adjusted for prognostic factors. SMM change was also assessed separately in weight-stable (<5%, i.e. occult SMM loss) patients. ResultsIn total, 1580 CT scans were analyzed, while a subset of 307 scans were analyzed in the fully-automated comparison. Included patients (n=553) had a mean age of 63±9 years and 39% were female. The semi-automated comparison revealed a bias of -2.41 cm2, 95% limits of agreement [-9.02 to 4.20], a WSCV of 2.25%, and an ICC of 0.99 (95% confidence intervals (CI) 0.97 to 1.00). The fully-automated comparison method revealed a bias of -0.08 cm2 [-10.91 to 10.75], a WSCV of 2.85% and an ICC of 0.98 (95% CI 0.98 to 0.99). Sensitivity and specificity for low muscle mass were 0.99 and 0.89 for the semi-automated comparison and 0.96 and 0.90 for the fully-automated comparison. SMM decrease was associated with shorter survival in both manual and automated assessment (n=78/280, HR 1.36 [95% CI 1.03 to 1.80] and n=89/280, HR 1.38 [95% CI 1.05 to 1.81]). Occult SMM loss was associated with shorter survival in manual assessment, but not significantly in automated assessment (n=44/263, HR 1.43 [95% CI 1.01 to 2.03] and n=51/2639, HR 1.23 [95% CI 0.87 to 1.74]). ConclusionDeep-learning based assessment of SMM at L3 shows reliable performance, enabling the use of CT measures to guide clinical decision making. Implementation in clinical practice helps to identify patients with low muscle mass or (occult) SMM loss who may benefit from lifestyle interventions.