Colon Cancer Cells Research Articles

Kaempferol promotes apoptosis and inhibits proliferation and migration by suppressing HIF-1α/VEGF and Wnt/β-catenin activation under hypoxic condition in colon cancer

A naturally occurring flavonoid compound found in several fruits and vegetables, kaempferol has garnered interest for its potential anticancer effects. The present investigation illustrates that kaempferol has multi-faceted anti-tumor effects in hypoxic colon cancer cells, HCT-15 (ATCC) and HCT-116 (KCLB) by inhibiting HIF-1α/VEGF angiogenesis, Wnt/β-catenin signaling, and epithelial-mesenchymal transition (EMT) progression. In conditions of hypoxia, kaempferol inhibited the stabilization of HIF-1α and its downstream targets (VEGF, ANG1, VEGFR2), while also obstructing Wnt/β-catenin activation by decreasing β-catenin and modifying the expression of pathway components (c-Myc, Cyclin-D1, LEF1, APC, and Axin-2). Kaempferol mitigated hypoxia-induced EMT by reinstating E-cadherin and inhibiting N-cadherin, Vimentin, and MMP-2/9, which corresponded with diminished migration in transwell and wound-healing assay. Mechanistic investigations demonstrated dual regulation of HIF-1α transcriptional activity (HRE luciferase) and MAPK signaling (p-ERK/p-38), in conjunction with ROS-induced DNA damage and intrinsic apoptosis (cleaved caspase-3/9 and Bcl-2 protein expression). The impact on angiogenesis, EMT, and survival pathways significantly diminished the proliferation, invasion, and metastatic capacity of hypoxic colon cancer cells which identifies kaempferol as an innovative multi-pathway inhibitor, thereby offering a strong justification for its advancement as a therapeutic agent for advanced colorectal cancer.Graphical abstract

Novel 8-Hydroxyquinoline-Derived V(IV)O, Ni(II), and Fe(III) Complexes: Synthesis, Characterization, and In Vitro Cytotoxicity Against Tumor Cells

We report the synthesis and characterization of five novel metal complexes. Three of them are vanadium complexes with the general formula [VO(Ln)2], where Ln are Schiff bases derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with either 4-(2-aminoethyl)morpholine (L1), 3-morpholinopropylamine (L2) or 1-(2-aminoethyl)piperidine (L3). The two other metal complexes are [Ni(L1)2] and [Fe(L1)2]Cl. They were characterized by analytical, spectroscopic (Fourier transform infrared, UV-visible absorption), and mass spectrometric techniques as well as by single-crystal X-ray diffraction (for all [VO(Ln)2] complexes and [Ni(L1)2]). While, in the crystal structure, the V(IV)O complexes show distorted square–pyramidal geometry with the ligands bound as bidentate through quinolate NO donors, the Ni(II) complex shows octahedral geometry with two ligand molecules coordinated through NNO donors. Stability studies in aqueous media revealed that the vanadium complexes are not stable, undergoing oxidation to VO2(L), which was corroborated by 51V NMR and MS. This behavior is also observed in organic media, though at a significantly slower rate. The Ni complex exhibited small spectral changes over time in aqueous media. Nonetheless, all compounds show enhanced stability in the presence of bovine serum albumin (BSA). Fluorescence studies carried out for the Ni(II) and Fe(III) complexes indicate reversible binding to albumin. The cytotoxicity of the L1 metal complexes was assessed on melanoma (B16F10 and A375) and colon cancer (CT-26 and HCT-116) cell lines, with 5-fluorouracil (5-FU) as a reference drug. The V- and Ni complexes showed the lowest IC50 values (<10 μM) in either A375 or HCT-116 cells after 48 h of incubation, while the Fe(III) complex presented minimal antiproliferative effects. The complexes were generally more cytotoxic to human than murine cancer cells. Synergistic in vitro studies with 5-FU revealed antagonism in most cases, except in A375 cells, where an additive effect was observed for the combination with the V-complex. Overall, these compounds show promising potential for cancer treatment, mostly for melanoma.

Depletion of oxysterol-binding proteins by OSW-1 triggers RIP1/RIP3-independent necroptosis and sensitization to cancer immunotherapy.

Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.

Exosomal miR-122-5p for regulation of secretory functions of fibroblasts and promotion of breast cancer metastasis by targeting MKP-2: an experimental study

ABSTRACT Tumor metastasis is a major obstacle for the effective treatment of breast cancer. Some studies showed that exosomes could promote tumor distant metastasis by establishing pre-metastasis niches (PMN). MicroRNAs (miRNAs) in exosomes play a critical role in tumor development and invasion. We aimed to investigate the effects of exosomal miRNAs derived from breast cancer cells on metastasis. MiRNA sequencing and RT-PCR approach were used to screen potential exosomal miRNAs. We compared the levels of serum exosomal miRNAs from breast cancer patients and those from MCF10A/MCF7/MDA-MB-231 cells. We found that differential exosomal miRNAs screened from patients with metastasis have higher expression levels in exosomes secreted by MDA-MB-231 cells. Using miRNA mimics or inhibitors, exosomal miR-122-5p was found to enhance the secretion levels of chemokine MCP-1 and SDF-1 from WI-38 lung fibroblast cells. In vitro luciferase assay and western blot confirmed the targeting of 3’-untranslated region of MKP-2 and suppression of MKP-2 expression by miR-122-5p in WI-38 cells. Treatment of xenograft mice with exosomal miR-122-5p increased the levels of MCP-1 and SDF-1 in serum, and promoted lung metastasis of breast cancer. In conclusion, we identified exosomal miR-122-5p from breast cancer cells that could promote the chemokine secretion of lung fibroblasts, which might facilitate the chemotaxis and colonization of breast cancer cells in lung tissue.

Cytotoxicity of L-asparaginase from eucaryotic Cladosporium species against breast and colon cancer in vitro

BackgroundRecent statistical analyses indicate a rapid increase in the incidence of breast and colon cancer in Egypt. Although invasive techniques have been widely employed for early detection, diagnosis, and intervention of those cancers, they are associated with inherent risks and limitations, which often result in various complications. Therefore, noninvasive screening methods are inevitable due to their accessibility, cost-effectiveness, and high patient compliance rates. The enzyme L-asparaginase catalyzes the conversion of L-asparagine to L-aspartic acid: key metabolite for tumor cell division, thereby demonstrating anticancer potential. However, the prolonged use of bacterial L-asparaginase may cause allergic reactions and side effects such as diabetes, leukopenia, and co-agglutination disorders. Exploring the anticancer properties of L-asparaginase from different species such as yeast and fungi has been proposed to mitigate these adverse effects.ObjectivesThis study aimed at extracting and optimizing the expression of L-asparaginase from the eukaryotic Cladosporium species, as to assess its anticancer potential against breast and colon cancer cell lines.MethodCladosporium species were identified morphologically and then cultured on modified Czapek-Dox Agar (mCDA) medium supplemented with L-asparagine to induce L-asparaginase production. Submerged fermentation was employed to optimize enzyme production. The enzyme activity was quantified using the Nesslerization method, and its cytotoxicity against colon and breast cancer cell lines was assessed using the (MTT) assay.ResultsAmong the Cladosporium isolates, 18.4% exhibited positive plate assay test, with enzyme activities ranging from 255 to 428 U/mL. Immunoblotting using sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed single protein band of approximately 37 kDa, consistent with L-asparaginase activity. Cytotoxicity assay of purified L-asparaginase showed significant antiproliferative effects against breast cancer cell lines MCF-7 and MDA-MB-231, with IC50 values of 36.26 and 45.7 µg/mL, respectively.ConclusionCertain eukaryotic Cladosporium strains are potential sources for the anticancer L-asparaginase production.Graphical Microbial L-asparaginase is one of the most important industrial enzymes of interest accounting for about 40 % of the total worldwide enzyme sales, this enzyme has got much significance in the medical field for the treatment of leukemia especially acute lymphoblastic leukemia (ALL).

Constructing a mitochondrial-related genes model based on machine learning for predicting the prognosis and therapeutic effect in colorectal cancer

The role of mitochondria in tumorigenesis and progression is has been increasingly demonstrated by numerous studies, but its prognostic value in colorectal cancer (CRC) remains unclear. To address this, we developed a mitochondrial-related gene prognostic model using 101 combinations of 10 machine learning algorithms. Patients in the high-risk group exhibited significantly shorter overall survival time. The high-risk group exhibited elevated tumor immune dysfunction and exclusion score, indicating diminished immunotherapy efficacy. To address the suboptimal treatment outcomes in these patients, we identified PYR-41 and pentostatin as potential therapeutic agents, which are anticipated to enhance therapeutic efficacy in the high-risk group. Additionally, four biomarkers (HSPA1A, CHDH, TRAP1, CDC25C) were validated by quantitative real-time PCR, with significant expression differences between normal intestinal epithelial cells and colon cancer cells. Our prognostic model provides accurate CRC outcome prediction and guides personalized therapeutic strategies.

Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells.

Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells.

GW501516 facilitated tumor immune escape by inhibiting phagocytosis.

GW501516 facilitated tumor immune escape by inhibiting phagocytosis.

MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.

MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.

Exploring the Molecular Targets and Therapeutic Potential of Coptisine in Colon Cancer: A Network Pharmacology Approach.

Colon cancer is a frequent malignancy, and surgery is still the primary therapy for people with colon cancer. Other treatments, including radiation, chemotherapy, and biologic therapy, may be utilized as a supplement. Chemotherapy, a prominent treatment for colon cancer, has failed to provide positive outcomes. This necessitates the development of more effective and less harmful treatment drugs. Coptisine was discovered to inhibit the development of colon cancer cell line HCT-116 in vivo, decrease the growth of HCT-116 cells, and cause apoptosis in vitro in colon cancer. Coptisine (COP) has shown antitumor activity in colon cancer, but its molecular mechanism and its molecular targets have not been fully understood. In this study, the biological behavior was verified in vitro. The targets of Huanglian alkaloids on colon cancer were predicted, and the protein-protein interaction (PPI) network was constructed. The core targets of safranine for colon cancer were extracted and analyzed by GO and KEGG enrichment to identify the possible molecular mechanisms of safranine treatment. Western blot was used to detect the changes of related pathway proteins in colon cancer cells. The differential expression of hub genes in colon cancer was analyzed using the GEPIA2 website. The binding ability of safranine to the target was verified by molecular docking. Finally, the targets were preliminarily verified by q-PCR analysis. Coptisine can inhibit the survival, migration, and proliferation of colon cancer cells DLD1 and HCT-116. Based on network pharmacology, ninety-one targets for colon cancer were screened. ESR1, ALB, AR, CDK2, PARP1, HSP90AB1, IGF1R, CCNE1, and CDC42 were found in the top 10. Enrichment analysis showed that these targets were mainly related to pathways in cancer, FC γ R-mediated phagocytosis, prostate cancer, progesterone-mediated oocyte maturation, the oestrogen signal pathway, proteoglycan in cancer and the PI3K-Akt signal pathway. WB results showed that after the treatment of colon cancer DLD1 cells with coptisine, the expression of P-AKT and AKT decreased, that of its downstream protein Bcl-2 decreased, and that of BAX increased. Differential expression analysis of hub genes showed that CCNE1, CDK2, HSP90AB1, and CHEK2 were upregulated in colon cancer samples, and molecular docking showed that these targets had a good ability to bind to coptisine. After the treatment of colon cancer DLD1 cells with coptisine, q-PCR results showed that CCNE1 and HSP90AB1 were significantly downregulated, while CDK2 and CHEK2 had no significant changes. Coptisine may be a candidate drug for the treatment of colon cancer, and its therapeutic effect may be related to the cancer pathway and PI3K-Akt signalling pathway. CCNE1 and HSP90AB1 may be potential targets of coptisine in the treatment of colon cancer.

Mesenchymal stem cell-derived small extracellular vesicles as a delivery vehicle of oncolytic reovirus.

The oncolytic reovirus has demonstrated efficacy against various cancer types in preclinical and clinical studies. However, its anti-tumor activity is limited. This study aimed to develop a novel drug delivery system (DDS) using small extracellular vesicles (sEVs) derived from human adipose-derived mesenchymal stem cells to enhance the therapeutic potential of reovirus. sEVs, which offer distinct advantages over traditional systems such as nanoparticles due to their natural biocompatibility, low immunogenicity, ability to cross biological barriers, and cell-derived targeting properties, were engineered to encapsulate reovirus particles (sEVs-reo). The anti-tumor activity of sEVs-reo was evaluated using colorectal cancer cell lines HCT116 and SW480. Additionally, resistance to neutralizing antibodies, internalization by cancer cells, and efficacy against junctional adhesion molecule-A(JAM-A)-knockout colon cancer cells resistant to reovirus, generated via CRISPR/Cas9, were assessed. sEVs-reo encapsulated reovirus particles effectively, and at a concentration of 0.5μg/ml, reduced viable tumor cells by 60.3% in HCT116 and 42.5% in SW480. Remarkably, sEVs-reo exhibited significant efficacy even in the presence of neutralizing antibodies, including anti-σ1 antibodies and serum from reovirus-infected mice. sEVs-reo were rapidly internalized by cancer cells within 4h while exhibiting reduced immunogenicity relative to reovirus, and demonstrated significant anti-tumor activity against JAM-A-deficient colon cancer cells. This study demonstrates that sEVs-reo can address key challenges associated with oncolytic virotherapy. These findings support potential of sEVs as a novel and effective DDS for reovirus in colon cancer treatment, while offering a versatile platform to enhance the efficacy of other oncolytic viruses.

Apoptotic and anti-inflammatory effect of nisin-loaded sodium alginate-gum arabic nanoparticles against colon cancer cells.

Apoptotic and anti-inflammatory effect of nisin-loaded sodium alginate-gum arabic nanoparticles against colon cancer cells.

A novel electrochemical biosensor based on TiO2 nanotube array films for highly sensitive detection of exosomes.

A novel electrochemical biosensor based on TiO2 nanotube array films for highly sensitive detection of exosomes.

Optimization of fungal fermentation for the extraction of polyphenols from Flourensia cernua and its effect on cellular metabolism.

Optimization of fungal fermentation for the extraction of polyphenols from Flourensia cernua and its effect on cellular metabolism.

Synthesis, Structure, and Anticancer Activity of a Dinuclear Organoplatinum(IV) Complex Stabilized by Adenine

The dinuclear platinum(IV) compound {Pt(CH3)3}2(μ-I)2(μ-adenine) (abbreviated Pt2ad), obtained by treating cubic [PtIV(CH3)3(μ3-I)]4 with two equivalents of adenine, was isolated and structurally characterized by single crystal X-ray diffraction. The National Cancer Institute Developmental Therapeutics Program’s in vitro sulforhodamine B assays showed Pt2ad to be particularly cytotoxic against the central nervous system cancer cell line SF-539, and the human renal carcinoma cell line RXF-393. Furthermore, Pt2ad displayed some degree of cytotoxicity against non-small cell lung cancer (NCI-H522), colon cancer (HCC-2998, HCT-116, HT29, and SW-620), melanoma (LOX-IMVI, Malme-3M, M14, MDA-MB-435, SK-MEL-28, and UACC-62), ovarian cancer (OVCAR-5), renal carcinoma (A498), and triple negative breast cancer (BT-549, MDA-MB-231, and MDA-MB-468) cells. Although anticancer studies involving some adenine platinum(II) compounds have been reported, this study marks the first assessment of the anticancer activity of an adenine platinum(IV) complex.

Synthesis, molecular docking, and antiproliferative activity studies of bromine bearing Schiff bases.

Synthesis, molecular docking, and antiproliferative activity studies of bromine bearing Schiff bases.

HaloPROTAC3 treatment activates the unfolded protein response of the endoplasmic reticulum in nonengineered mammalian cell lines.

Proteins fused to HaloTag, an engineered haloalkane dehalogenase, can be depleted by a heterobifunctional degrader compound HaloPROTAC3. The binding of HaloPROTAC3 to both the HaloTag and the E3 ligase von Hippel-Lindau (VHL)brings them into proximity and mediates the degradation of the HaloTag fusion proteins. Here, we generated a colon cancer cell line HCT116 expressing HaloTag fused to the RNA-binding protein IGF2BP3 to study its function. HaloPROTAC3 treatment depleted 75% of HaloTag-IGF2BP3 in 5 h. Transcriptomics revealed that HaloPROTAC3 treatment resulted in the destabilization of IGF2BP3 target mRNAs and activated the unfolded protein response (UPR). Surprisingly, we found that HaloPROTAC3 results in UPR activation in nonengineered mammalian cells. Our data demonstrate that HaloPROTAC3 causes mild endoplasmic reticulum stress independent of IGF2BP3 function and shall guide future studies using the HaloPROTAC3 protein depletion strategy.

Active Substances from the Micro-Immunotherapy Medicine 2LC1® Show In Vitro Anti-Cancer Properties in Colon, Prostate, and Breast Cancer Models and Immune-Enhancing Capabilities in Human Macrophages

Tumor-associated macrophages (TAMs) play a pivotal role in cancer regulation by influencing tumor growth, metastasis, and the immune microenvironment. By providing low doses and ultra-low doses (ULD) of immune regulators to the organism, micro-immunotherapy (MI) medicines (MIM) could be seen as valuable adjuvant drugs in the context of a wide range of pathological conditions, including cancers. Thus, these MIM could target TAMs, affecting their phenotype and activities. In this study, the anti-tumor and the immune-stimulatory effects of four capsules out of the ten composing the Labo’life’s MIM 2LC1® (2LC1-1, 2LC1-6, 2LC1-7, and 2LC1-8), as well as the specific nucleic acid (SNA®) sequence SNA-MYC present at ULD in this medicine have been evaluated in vitro, in several cancer models, and in human monocyte-derived macrophages. Our results showed that the tested MI formulations increased the tumor cell death of spheroids from HCT-116 colon cancer cells, while reducing the spheroid volume. Moreover, the treatments impaired the clonogenic capabilities of two cancer cell lines from epithelial origin, the LNCaP prostate cancer and the MCF-7 breast cancer cells. Interestingly, ULD of the SNA-MYC shared similar anti-cancer capabilities in those models, and it led to a significant reduction in the expression of C-MYC when evaluated in a model of human M2 macrophages. In the same model, the MI formulations also increased the expression of CD86 and HLA-DR, two markers of M1 anti-tumor macrophages. In addition, the tested items modulated the secretion of a panel of chemokines related to macrophage activity and immune cell recruitment. Finally, our results showed that 2LC1-8 increased the phagocytosis capabilities of human monocyte-derived macrophages, thus possibly contributing to sustaining the immune functions of M1, which are crucial in the context of cancer. Even if more research is needed to uncover their exact mechanism of action, these results suggest that the tested capsules of 2LC1 as well as ULD of SNA-MYC display both anti-tumor and immune-enhancing effects.

An inulin-type fructan CP-A from Codonopsis pilosula combined with 5-Fluorouracil alleviates colitis-associated tumorigenesis via inhibition of EGFR/AKT/ERK signaling pathway and regulation of intestinal flora.

An inulin-type fructan CP-A from Codonopsis pilosula combined with 5-Fluorouracil alleviates colitis-associated tumorigenesis via inhibition of EGFR/AKT/ERK signaling pathway and regulation of intestinal flora.

Molecular mechanisms underlying the anti-Colon Cancer effects of Caulerpa lentillifera polysaccharides (CLP).

Molecular mechanisms underlying the anti-Colon Cancer effects of Caulerpa lentillifera polysaccharides (CLP).