Human Colorectal HCT116 Cells Research Articles

Microfluidic Detection of Adenylate Kinase as a Cell Damage Biomarker

In vitro cell cultures are used as models for drug discovery. The detection of cell damage biomarkers such as adenylate kinase (AK) is often used in drug screening and cell biology experiments. A microfluidic platform for AK detection was developed with the capability of detecting the AK resulting from the lysis of 10–100 human colorectal adenocarcinoma HCT116 cells. For this assay, AK was captured on the surface of microbeads integrated into a microfluidic device and optically detected using a fluorescently labelled anti-AK antibody. Microfluidic technologies have in addition been used to develop two- and three-dimensional cell culture models that have the potential to accelerate drug discovery. The microfluidic platform was used to detect the AK resulting from the lysis of HCT116 cells cultivated in a microfluidic biochip, demonstrating the potential for the integration of the miniaturised biosensor with the cell chip.

Comparative Analyses of Fucoidans from South African Brown Seaweeds That Inhibit Adhesion, Migration, and Long-Term Survival of Colorectal Cancer Cells.

Human colorectal cancer (CRC) is a recurrent, deadly malignant tumour with a high incidence. The incidence of CRC is of increasing alarm in highly developed countries, as well as in middle to low-income countries, posing a significant global health challenge. Therefore, novel management and prevention strategies are vital in reducing the morbidity and mortality of CRC. Fucoidans from South African seaweeds were hot water extracted and structurally characterised using FTIR, NMR and TGA. The fucoidans were chemically characterised to analyse their composition. In addition, the anti-cancer properties of the fucoidans on human HCT116 colorectal cells were investigated. The effect of fucoidans on HCT116 cell viability was explored using the resazurin assay. Thereafter, the anti-colony formation potential of fucoidans was explored. The potency of fucoidans on the 2D and 3D migration of HCT116 cells was investigated by wound healing assay and spheroid migration assays, respectively. Lastly, the anti-cell adhesion potential of fucoidans on HCT116 cells was also investigated. Our study found that Ecklonia sp. Fucoidans had a higher carbohydrate content and lower sulphate content than Sargassum elegans and commercial Fucus vesiculosus fucoidans. The fucoidans prevented 2D and 3D migration of HCT116 colorectal cancer cells to 80% at a fucoidan concentration of 100 µg/mL. This concentration of fucoidans also significantly inhibited HCT116 cell adhesion by 40%. Moreover, some fucoidan extracts hindered long-term colony formation by HCT116 cancer cells. In summary, the characterised fucoidan extracts demonstrated promising anti-cancer activities in vitro, and this warrants their further analyses in pre-clinical and clinical studies.

Atractylenolide I inhibited the development of malignant colorectal cancer cells and enhanced oxaliplatin sensitivity through the PDK1-FoxO1 axis.

Colorectal cancer (CRC) is a type of ordinary malignancy of the gastrointestinal tract. Atractylenolide I (AT-I) has been shown to inhibit the process of CRC. However, the specific mechanism by which AT-I inhibits CRC is not yet well understood. Cell Counting Kit-8 and colony formation assays were conducted to examine cell proliferation. The cell apoptosis was detected by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL). Cell invasion and migration were evaluated by wound-healing and Transwell assay. The angiogenesis capabilities of the cells were examined by tube formation experiments. Western blot was conducted to examine the apoptosis and angiogenesis-associated proteins, pyruvate dehydrogenase kinase 1 (PDK1), and Forkhead box protein O1 (FoxO1) expression. We found that AT-I inhibited the proliferative, migratory and invasive abilities of Human colorectal cancer cell line HCT116 cells but stimulated cell death by promoting cell apoptosis via the PDK1/FoxO1 axis. In addition, the upregulation of PDK1 decreased the inhibitory effect of AT-I on HCT116 angiogenesis, and AT-I increased oxaliplatin sensitivity via the PDK1/FoxO1 axis. Collectively, AT-I inhibited the malignant development of CRC cells and increased oxaliplatin sensitivity by decreasing PDK1 and inhibiting FoxO1 phosphorylation. Thus, AT-I has protective potential and could be a promising agent for CRC treatment.

Synthesis and Biological Evaluation of Furyl-Carboxamide Derivatives as Potential Anticancer Agents

Topoisomerase II (Top-II) is an essential therapeutic target in cancer treatment owing to its overexpression in a wide variety of cancerous cells, including colorectal and breast cancer. Significant efforts have been made to discover and develop competitive inhibitors of the Top-II enzyme as potential anticancer agents. Herein, molecular modeling was employed to identify a new series of furyl-2-carboxamide derivatives as potential anticancer agents. Compounds 3, 5, and 7 were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectroscopy, as well as elemental analysis. The anticancer activity properties of compounds 3, 5, and 7 were evaluated in vitro using an MTT assay in a human colorectal HCT-116 cell line with different concentration dilutions. The results indicate that the anthraquinone compound 3 is 1.3-1.6 times more potent against human colon cancer HCT-116 cells than the pyridine and benzophenone compounds 7 and 5, respectively, which reveals the importance of the anthraquinone moiety in exerting the inhibitory activity of the compound. Our findings recommend that further optimization of this series would benefit colon cancer treatment.

The Chemosensitizing Effect of Portulaca oleracea Methanol Extract on Human Colorectal and Lung Cancer Cells Against Irinotecan

Cancer is a major health problem and it has been causing great damage in recent years worldwide. Serious side effects of chemotherapeutics used in cancer treatment make natural products valuable. Combined use of chemotherapy drugs and herbal products is an important approach in reducing side effects and revealing a more effective treatment. In this study, the effects of methanolic extract from Portulaca oleracea (POM) alone and in combination with Irinotecan were investigated against human colorectal carcinoma cell line HCT-116 and human lung adenocarcinoma cell line A549. The antiproliferative/anti-colony formation effects were determined using WST-1 assay and clonogenic assay. Cell death detection Elisa assay was employed to exhibite the triggered apoptosis, and quantitative real time polimerase chain reaction (qRT-PCR) was performed to evaluate the mRNA expression of mTOR, Akt and PTEN genes, which are significant modulators of apoptotic and survival pathways. It was determined that 72 h treatment with increasing concentrations of POM (0-1000 mg mL-1) decreased the viability of HCT116 and A549 cells in a dose-dependent manner. Also, POM and Irinotecan exhibited synergistic effects in both cell lines. The combination of POM and Irinotecan suppressed the colony forming capacity of HCT116 and A549 cells by 84% and 79%, respectively. POM also altered mTOR, Akt and PTEN gene expressions in HCT-116 and A549 carcinoma cells, both alone and in combination with Irinotecan. This study shows that the phytotherapeutic effect of P. oleracea needs to be studied more intensively.

Nanoencapsulation of apigenin with whey protein isolate: Physicochemical properties, in vitro activity against colorectal cancer cells, and bioavailability

Incorporating lipophilic phytochemicals with anti-cancer activities in functional beverages requires an appropriate nanoencapsulation technology. The present objective was to encapsulate apigenin with whey protein isolate (WPI) utilizing a pH-cycle method and subsequently characterize physicochemical properties, the in vitro anticancer activities against human colorectal HCT-116 and HT-29 cancer cells, and the in vivo bioavailability. Up to 2.0 mg/mL of apigenin was nanoencapsulated with 1.0 mg/mL WPI, with an encapsulation efficiency of up to 98.15% and loading capacity of up to 196.21 mg/g-WPI. Nanodispersions were stable during storage, and apigenin became amorphous after encapsulation. Nanoencapsulation and in vitro digestion did not reduce the anti-proliferative activity of apigenin. Nanoencapsulation of apigenin enhanced the cellular uptake, the pro-apoptotic effects, and the bioavailability in the mice's blood and colon mucosa when comparing to the unencapsulated apigenin. Therefore, the present work may be significant to incorporate lipophilic phytochemicals in functional beverages for disease prevention.

Synthesis, spectral characterization, DFT calculations, pharmacological studies, CT-DNA binding and molecular docking of potential N, O-multidentate chelating ligand and its VO(II), Zn(II) and ZrO(II) chelates

The pharmacological efficacy of the variety tetradentate ligands encouraged us to design attractive compounds through effective synthetic procedure. The prepared Schiff base ligand 6,6′-((1E,1′E)-((4-chloro-1,2-phenylene)bis(azaneylylidene))bis(methaneylylidene))bis(2-ethoxy phenol (H2L), which derived from 4-chloro-o-phenylenediamine and 3-ethoxy-salicylaldehyde and its VO(II), Zn(II) and ZrO(II) metal chelates, have been synthesized and characterized with aim of that it may struggle the invasion of drug resistance. The chemical structural of studied compounds were discussed by TGA, elemental analysis, UV–Vis., 1H NMR, 13C NMR, FTIR, mass spectral, PXRD, molar conductance, magnetic susceptibility measurements and density functional theory. The results assigned square pyramid geometries for [VOL] and [ZrOL].2H2O chelates and an octahedral geometry for [ZnL(H2O)2].2H2O chelate. Powder XRD data showed that the complexes are monoclinic with polycrystalline nature. The results of CT-DNA interaction with the titled chelates showed that the binding between CT-DNA and the metal complexes occurs through intercalation mode. Their CT-DNA binding efficiency estimated in terms of their binding constants (Kb), which gave the order: VOL (6.9 × 105) > ZrOL (6.3 × 105) > ZnL(H2O)2 (5.5 × 105). The antimicrobial activities of the synthesized compounds were tested against selected fungal and bacterial strains using well diffusion technique. The obtained chelates showed higher antifungal and antibacterial activities than their corresponding ligand. Furthermore, the M−complexes showed higher potent cytotoxic effect toward HEK-293, human colorectal HepG-2, HCT-116 and MCF-7 adenocarcinoma cell lines compared to the free H2L ligand. Investigation of antioxidant property represented that all the prepared complexes have better radical scavenging potencies against DPPH radicals than the free H2L ligand. To study the molecular docking of proposed compounds versus Tyrosine kinases receptor (TKR), we used AutoDock1.5.6rc3® suite. The current compounds (H2L, VOL, ZrOL and ZnL(H2O)2) and STI were found to bind with C-kit of TKR with HBs at ILE789.A, ILE808.A, ASP810.A, GLU640.A and TYR846 amino acid residue and the binding energies were − 8.9, −8.93, −8.83, −1.48 and −10.39 kcal/mol respectively.

An Efficient Synthesis of Novel Dextran-Arsenite Nanoparticles intended for Potential Antitumor Drug Material.

The functionalization of polysaccharides with synthetic nanopolymers has attracted great attention owing to the applications of this method in many industrial fields. This work aimed to investigate the effect of arsenic trioxide on the functionalization of dextran. Dextran-arsenite nanoparticle formation was induced by microwave with sulfuric acid as a catalyst. Various analytical techniques were used to verify the structure of the nanopolymers. Besides, various reaction conditions, such as dextran concentration, arsenic trioxide concentration and pH, were investigated to determine their impact on particle size. The results indicated that the product was an arsenite-based nanomaterial retaining the basic configuration of dextran and that the product size was positively correlated with pH but negatively correlated with arsenic trioxide concentration. Moreover, the inhibitory effects of the dextran-arsenite nanoparticles on the growth of the human colorectal cancer cell line HCT-116 and human hepatoma carcinoma cell lines Huh-7 and SMMC-7721 were studied. The results showed that the product could inhibit the proliferation of these three tumor cell lines in a dose-dependent manner. Therefore, the product could be a new type of functional nanomaterial for further study on the synthesis, biological activity and development of polysaccharide drugs.

Synergistic anti-cancer effect of pristimerin and docetaxel on human colorectal HCT-116 cells

• Pristimerin synergized the anticancer activities of docetaxel in colon cancer cells. • Pristimerin potentiated the cytotoxicity and apoptosis-inducing effects of docetaxel. • Pristimerin may reduce the chemoresistance of cancer cells toward anticancer agents. Pristimerin is a quinonemethide triterpenoid compound that exerts anticancer activities against different cancer cells, including colorectal cancer. The current study aimed to study the cytotoxic and apoptosis-inducing effects of pristimerin alone or in combination with docetaxel on HCT-116 human colorectal cancer cell line. The cytotoxicity of pristimerin, or docetaxel, or the combination on HCT-116 cells were measured using the MTT method. The combination index (CI) was calculated using the isobologram method of Chou and Talalay. Annexin V/PI double staining was used to assess the apoptosis-inducing effect of these agents. Our results showed that both pristimerin and docetaxel showed potent cytotoxic effects against HCT-116 cells in dose-dependent manners. Moreover, the efficacy of docetaxel combined pristimerin was significantly increased, compared to individual treatment. The CI value was (0.55 to 0.89) that indicated the synergistic interaction between two agents to inhibit cell growth of CRC cells. Furthermore, Annexin V/PI assay showed that both agents induced apoptosis in HCT-116 in cancer cells. While treatment with combination resulted in a significant enhancement in apoptosis rates compared to individual treatment. Collectively, the data indicated that pristimerin potentiated the anticancer activities of docetaxel in colon cancer cells by reducing cell viability and promoting apoptosis.

Influence of bifentrin, a pyrethriod pesticide, on human colorectal HCT-116 cells attributed to alterations in oxidative stress involving mitochondrial apoptotic processes

ABSTRACT The widespread use of pesticides is beneficial for food production; however, there are numerous adverse consequences reported in the ecosystem and humans associated with exposure to these contaminants. The pyrethriod bifenthrin (BIF) is utilized for (1) maintenance, growth, and storage of agricultural products; (2) control of internal and external parasites of farm animals; and (3) eradication of insects threatening public health. Numerous data are available regarding environmental and ecological impact of pyrethriods on the central and peripheral nervous systems; however few studies focused on non-target tissues especially in humans. Therefore, the aim of this investigation was to determine the potential cytotoxic effects of BIF on a non-target tissue using human colorectal HCT-116 cells as a model. Data demonstrated that BIF reduced cell viability and disrupted mitochondrial functions which were accompanied by increased reactive oxygen species (ROS) levels indicating the presence of oxidative stress. BIF produced a significant elevation in levels of malondialdehyde (MDA) supporting the role of oxidative stress in pesticide-mediated toxicity. Concomitantly, a fall of mitochondrial transmembrane potential (Δψ), consequently producing perturbation of fluidity as well as excitability of cellular membranes was noted. Our results also indicated that BIF induced a rise in DNA damage as evidenced by the comet assay. An increase in mitogen-activated protein kinases (MAPKs), JNK (N-terminal Kinase), p38, and ERK (extracellular-signal-regulated kinase) suggested an apoptotic effect. Data thus indicated that BIF-induced cytotoxicity in human colorectal HCT-116 cells was associated with oxidative stress, mitochondrial dysfunction, and apoptosis.

Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress.

Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the antiproliferative effect of acridine chalcone 1C ((2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one) in human colorectal HCT116 cells. We demonstrated that chalcone 1C induced oxidative stress via increased reactive oxygen/nitrogen species (ROS/RNS) and superoxide production with a simultaneous weak adaptive activation of the cellular antioxidant defence mechanism. Furthermore, we also showed chalcone-induced mitochondrial dysfunction, DNA damage, and apoptosis induction. Moreover, activation of mitogen activated phosphokinase (MAPK) signalling pathway in 1C-treated cancer cells was also observed. On the other hand, co-treatment of cells with strong antioxidant, N-acetyl cysteine (NAC), significantly attenuated all of the above-mentioned effects of chalcone 1C, that is, decreased oxidant production, prevent mitochondrial dysfunction, DNA damage, and induction of apoptosis, as well as partially preventing the activation of MAPK signalling. Taken together, we documented the role of ROS in the antiproliferative/pro-apoptotic effects of acridine chalcone 1C. Moreover, these data suggest that this chalcone may be useful as a promising anti-cancer agent for treating colon cancer.

Calcium Delivery by Electroporation Induces In Vitro Cell Death through Mitochondrial Dysfunction without DNA Damages.

Adolescent cancer survivors present increased risks of developing secondary malignancies due to cancer therapy. Electrochemotherapy is a promising anti-cancer approach that potentiates the cytotoxic effect of drugs by application of external electric field pulses. Clinicians proposed to associate electroporation and calcium. The current study aims to unravel the toxic mechanisms of calcium electroporation, in particular if calcium presents a genotoxic profile and if its cytotoxicity comes from the ion itself or from osmotic stress. Human dermal fibroblasts and colorectal HCT-116 cell line were treated by electrochemotherapy using bleomycin, cisplatin, calcium, or magnesium. Genotoxicity, cytotoxicity, mitochondrial membrane potential, ATP content, and caspases activities were assessed in cells grown on monolayers and tumor growth was assayed in tumor spheroids. Results in monolayers show that unlike cisplatin and bleomycin, calcium electroporation induces cell death without genotoxicity induction. Its cytotoxicity correlates with a dramatic fall in mitochondrial membrane potential and ATP depletion. Opposite of magnesium, over seven days of calcium electroporation led to spheroid tumor growth regression. As non-genotoxic, calcium has a better safety profile than conventional anticancer drugs. Calcium is already authorized by different health authorities worldwide. Therefore, calcium electroporation should be a cancer treatment of choice due to the reduced potential of secondary malignancies.

Reinvestigation of Disulfide-bonded Oligomeric Forms of the Unfolded Protein Response Transducer ATF6.

ATF6α is an endoplasmic reticulum (ER)-embedded transcription factor which is rapidly activated by ER stress, and a major regulator of ER chaperone levels in vertebrates. We previously suggested that ATF6α occurs as a monomer, dimer and oligomer in the unstressed ER of Chinese hamster ovary cells due to the presence of two evolutionarily conserved cysteine residues in its luminal region (C467 and C618), and showed that ATF6α is reduced upon ER stress, such that only reduced monomer ATF6α is translocated to the Golgi apparatus for activation by proteolysis. However, mutagenesis analysis (C467A and C618A) revealed that the C618A mutant behaves in an unexpected manner (monomer and oligomer) during non-reducing SDS-PAGE, for reasons which remained unclear. Here, we used human colorectal carcinoma-derived HCT116 cells deficient in ATF6α and its relevant ATF6β, and found that ATF6α dimer and oligomer are both dimers, which we designated C618-dimer and C467-dimer, respectively. We demonstrated that C467-dimer (previously considered an oligomer) behaved bigger than C618-dimer (previously considered a dimer) during non-reducing SDS-PAGE, based on their disulfide-bonded structures. Furthermore, ATF6α monomer physically associates with another ATF6α monomer in the absence of disulfide bonding, which renders two C467 residues in close proximity so that formation of C467-dimer is much easier than that of C618-dimer. In contrast, C618-dimer is more easily reduced upon ER stress. Thus, our analysis revealed that all forms of ATF6α, namely monomer, C618-dimer and C467-dimer, are activated by single reduction of a disulfide bond in response to ER stress, ensuring the rapidity of ATF6α activation.Key words: disulfide-bonded structure, endoplasmic reticulum, membrane-bound transcription factor, non-reducing SDS-PAGE, unfolded protein response.

Synthesis and cytotoxic activity of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group as the A-ring or B-ring.

Many natural or synthetic chalcones have potential anti-tumor activity. Here, we synthesized two series of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group and evaluated for their cytotoxic activity towards cultured human lung cancer A549 and colorectal HCT-116 cells. Among them, compound 8d was the most cytotoxic against HCT-116 cells, with an IC50 value of 2.65 μM. Analyses of the phenotypic changes induced by this compound found a dose-dependent accumulation of HCT-116 cells in sub-G1 phase, indicating that compound 8d might induce apoptosis. Furthermore, we found that 8d triggered mitochondrial membrane potential depolarization, promoted reactive oxygen species formation in HCT-116 cells, and increased the percentage of early and late apoptotic cells. Finally, immunoblotting indicated that 8d increased PARP-1 and caspases 3, 7 and 9 cleavage. These data suggest that compound 8d induces apoptosis via the mitochondrial death pathway.

Eugenol protects against citrinin-induced cytotoxicity and oxidative damages in cultured human colorectal HCT116 cells.

This study aimed to investigate the protective effects of Eugenol (EUG), an effective antioxidant phenolic compound with a radical scavenging activity against citrinin (CTN)-induced toxicity in vitro using HCT116 cells. CTN is a well-known mycotoxin found in different constituents of the food chain. This environmental contaminant produces free radicals which interacts with cellular macromolecules and produces oxidation of protein, lipid, and DNA. The cytotoxic effects were monitored by measuring cell viability, reactive oxygen species (ROS) generation, antioxidant enzyme activities, malondialdehyde (MDA) production, protein oxidation, and DNA fragmentation. Our results have shown that the pretreatment of HCT116 cells with EUG, 2 h prior to citrinin (CTN) exposure, significantly decreased CTN-induced cell death, inhibited ROS generation, modulated activities of both catalase (CAT) and superoxide dismutase (SOD), and reduced MDA production. Level of protein-bound sulfhydryls and DNA fragmentation were also declined as compared with CTN-treated cells. These findings suggest that EUG would be an effective protective agent against CTN-induced oxidative stress, and thereby, it may complement and add to the functions of antioxidant vitamins and enzymes as a protection against the cytotoxicity of this mycotoxin.

Impact of p53 function on the sulfotransferase-mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1-hydroxymethylpyrene in vitro.

The tumor suppressor p53, encoded by TP53, is known as the "guardian of the genome." Sulfotransferases (SULTs) are involved in the metabolism of alkylated polycyclic aromatic hydrocarbons such as 1-hydroxymethylpyrene (1-HMP), which is a known substrate for SULT1A1. To investigate the impact of TP53 on the metabolic activation of 1-HMP, a panel of isogenic human colorectal HCT116 cells having TP53(+/+), TP53(+/-), or TP53(-/-) were treated with 10 μM 1-HMP for 24 hr. 1-HMP-DNA adduct formation was determined by ultraperformance liquid chromatography-tandem mass spectrometry analysis, which quantified two nucleoside adducts N2 -(1-methylpyrenyl)-2'-deoxyguanosine and N6 -(1-methylpyrenyl)-2'-deoxyadenosine. 1-HMP treatment resulted in significantly (~40-fold) higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. Higher levels of 1-HMP-induced DNA adducts in TP53(+/+) cells correlated with higher basal expression of SULT1A1/3 in this cell line, but 1-HMP treatment showed no effect on the expression of this protein. These results indicate that the cellular TP53 status is linked to the SULT1A1/3-mediated bioactivation of 1-HMP, thereby broadening the spectrum of p53's targets. Environ. Mol. Mutagen., 60:752-758, 2019. © 2019 Wiley Periodicals, Inc.

Chemical Analysis and Cytotoxic and Cytostatic Effects of Twelve Honey Samples Collected from Different Regions in Morocco and Palestine.

The aim of this in vitro study is to characterize the phenolic compounds of twelve honey samples collected from different locations in Palestine (H1-6) and Morocco (H7-12) and to evaluate their cytotoxic and cytostatic effects in cells from the human colorectal carcinoma cell line HCT-116 and breast cancer cell line MCF-7. Quantitative HPLC analysis revealed nine phenolic compounds in three Moroccan honey samples, namely, syringic acid, tannic acid, caffeic acid, ferulic acid, coumaric acid, gallic acid, rosmarinic acid, epicatechin, and pyrogallol. Syringic acid, abundant in numerous types of honey with strong antioxidant capacities, was present at values ranging between 0.10 mg/100 g and 1.24 mg/100 g of Daghmos (H11) and Kabbar (H10) samples, respectively. No significant reductions in cell viability were observed in both cell lines treated with the Palestinian samples as measured with MTT assay. Significant cytostatic effects were after treatment of HCT cells with Morar honey H1 with IC50 of 1789 μg/ml. Three Moroccan samples, H7 (Zaâtar), H9 (Bochnikha), and H10 (Kabbar), showed slight, but significant cytostatic effects in HCT cells. A strong correlation was observed between cytostatic activity of MCF cells and antioxidant content (phenols, flavonoids, and flavonol). Furthermore, a strong negative correlation was detected between the cytostatic activity in HCT cells and the contents of syringic acid (r= -0.756) and tannic acid (r= -0.610). These results indicate that the traditionally known anticancer effects of honey might be mediated in part through cytostatic effects.

Systemic miRNA delivery by nontoxic nanoscale coordination polymers limits epithelial-to-mesenchymal transition and suppresses liver metastases of colorectal cancer

Though early detection and treatment of primary tumors has significantly improved in recent years, metastatic disease remains among the most significant challenges in cancer therapy. Cancer cells can disseminate before the primary tumor is detected to form micro or gross metastases, requiring toxic systemic therapies. To prevent and suppress metastases, we have developed a nontoxic, long-circulating nanoscale coordination polymer (NCP) protecting microRNA (miRNA) in circulation and releasing it in tumors. PtIV(en)2 [en = ethylenediamine] containing NCPs (PtEN) can release a nontoxic, kinetically inert PtII(en)2 compound and carbon dioxide which aids the endosomal escape of its miRNA cargo, miR-655-3p. Without the presence of the PtEN core, the miRNA showed cellular uptake but no effect. When transfected into human colorectal HCT116 cells by NCPs, this oligometastatic miRNA limited proliferation and epithelial-to-mesenchymal transition by preventing β-catenin nuclear translocation and tumor cell invasion. Systemic administrations of PtEN/miR-655-3p sustained effective transfection to reduce liver colonization and tumor burden in a xenogenic hepatic metastatic model of HCT116 without any observable toxicity.

Luteolin Shifts Oxaliplatin-Induced Cell Cycle Arrest at G₀/G₁ to Apoptosis in HCT116 Human Colorectal Carcinoma Cells.

Certain antioxidative flavonoids are known to activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates cellular antioxidants and detoxifying response and is reportedly highly activated in many types of cancers. Few studies on the potential undesired effects of flavonoid intake during chemotherapy have been conducted, yet Nrf2 activators could favor cancer cell survival by attenuating chemotherapeutic efficiency. This study aimed to examine if luteolin, an Nrf2 activator, hinders chemotherapeutic activity of oxaliplatin, a potent anticancer agent for colorectal cancer, in HCT116 cells. Luteolin treatment strongly increased the transcriptional activity of the antioxidant response element in HCT116 cells and induced the protein expression of heme oxygenase-1, which were indicative of its Nrf2-inducing potential. Intriguingly, 25 μM luteolin reduced cell viability through apoptotic induction, which was intensified in p53-expressing cells while 1 μM oxaliplatin caused cell cycle arrest at G0/G1-phase via the p53/p21-dependent mechanism. Moreover, luteolin treatment was found to reduce oxaliplatin-treated p53-null cell viability and colony counts further, thereby demonstrating an additional effect of luteolin in the killing of human colorectal tumor HCT116 cells not expressing functional p53 protein. The findings suggest that luteolin can induce p53-mediated apoptosis regardless of oxaliplatin treatment and may eliminate oxaliplatin-resistant p53-null colorectal cells.

Anti-proliferative and Pro-apoptotic Activities of Nelumbo nucifera and Neferine in Human Colorectal HCT116 Cells

Anti-proliferative and Pro-apoptotic Activities of Nelumbo nucifera and Neferine in Human Colorectal HCT116 Cells