Search Results (56)

The dinuclear platinum(IV) compound {Pt(CH₃)₃}₂(μ-I)₂(μ-adenine) (abbreviated Pt₂ad), obtained by treating cubic [Pt^IV(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. Full article

Colorectal cancer (CRC) ranks among the most frequently diagnosed malignancies and is associated with a significantly high mortality rate. In recent years, increasing attention has been directed toward naturally derived substances with anticancer properties. In our study, we focused on determining the biological and antibacterial effects of selected essential oils (EOs)—peppermint, oregano, tea tree, lemon, lavender, frankincense, and oil blends (Zengest and OnGuard). Analyses were performed on human colon carcinoma cell lines (HCT-116 and HT-29). The cytotoxic (MTT assay), genotoxic effects (comet assay), and reactive oxygen species levels (ROS-Glo™ H₂O₂ Assay) of EOs and oil blends were determined. In our study, we found that all of the studied oils have the potential cyto/genotoxic effects on CRC cell lines after 24 h exposure. The results revealed that oregano, Zengest, and frankincense showed statistically the highest cytotoxic effects [IC₅₀ 0.05 µg/mL] compared to the other studied oils. These oils induced DNA damage and also increased ROS levels. On the other hand, peppermint was shown to have the lowest cytotoxic effect [IC₅₀ 0.67 µg/mL] on the HT-29 cell line. We also evaluated the antibacterial effects of oregano, tea tree, and the OnGuard blend, determining their impact on the viability of beneficial bacteria models, including Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, Lacticaseibacillus paracasei, Lactobacillus brevis, Lactobacillus pentosus, and Weizmannia coagulans. Oregano exhibited strong antibacterial activity, with an inhibition zone of 31 mm, while tea tree and OnGuard showed inhibition zones ranging from 12 to 15 mm. The EOs (oregano, tea tree, OnGuard) demonstrated antibacterial effects, with MICs ranging from 0.05 to 0.5 µg/mL. Peppermint, lemon, lavender, frankincense, and the Zengest blend did not inhibit the growth of lactic acid bacteria or W. coagulans, and thus did not impact bacterial survival. On the other hand, they demonstrated potential anticancer effects. Full article

Background: The pyrrolobenzodiazepine (PBD) dimer SJG-136 reached Phase II clinical trials in ovarian cancer and leukaemia in the UK and USA in the 2000s. Several structural analogues of SJG-136 are currently in clinical development as payloads for Antibody-Drug Conjugates (ADCs). There is growing evidence that PBDs exert their pharmacological effects through inhibition of transcription factors (TFs) in addition to arrest at the replication fork, DNA strand breakage, and inhibition of enzymes including endonucleases and RNA polymerases. Hence, PBDs can be used to target specific DNA sequences to inhibit TFs as a novel anticancer therapy. Objective: To explore the ability of SJG-136 to bind to the cognate sequences of transcription factors using a previously described HPLC/MS method, to obtain preliminary mechanistic evidence of its ability to inhibit transcription factors (TF), and to determine its effect on TF-dependent gene expression. Methods: An HPLC/MS method was used to assess the kinetics and thermodynamics of adduct formation between the PBD dimer SJG-136 and the cognate recognition sequence of the TFs NF-κB, EGR-1, AP-1, and STAT3. CD spectroscopy, molecular dynamics simulations, and gene expression analyses were used to rationalize the findings of the HPLC/MS study. Results: Notable differences in the rate and extent of adduct formation were observed with different DNA sequences, which might explain the variations in cytotoxicity of SJG-136 observed across different tumour cell lines. The differences in adduct formation result in variable downregulation of several STAT3-dependent genes in the human colon carcinoma cell line HT-29 and the human breast cancer cell line MDA-MB-231. Conclusions: SJG-136 can disrupt transcription factor-mediated gene expression, which contributes to its exceptional cytotoxicity in addition to the DNA-strand cleavage initiated by its ability to crosslink DNA. Full article

To enhance the treatment of tumors that are resistant to radio- and chemotherapy while minimizing the side effects of radiochemotherapy, researchers are continuously seeking new active compounds for use in combination with radiotherapy. Therefore, the aim of our study was to examine the cytotoxic and radiosensitizing effects of an extract from St. John’s Wort (Hypericum perforatum), referred to as HP01, on human epithelial tumor cells in vitro. The growth of MCF-7 (breast carcinoma) and HT-29 (colon carcinoma) cells was examined under the influence of HP01. In combination with radiation, the effects of HP01 on cytotoxicity and long-term survival were assessed using a colony formation assay. The number of DNA double-strand breaks was analyzed using the γH2AX assay, while cell cycle distribution was examined via flow cytometry. A growth-inhibiting and cytotoxic effect was observed for both tumor cell lines starting at a concentration of 10 µg/mL HP01. Treatment with HP01 resulted in an inhibition of clonogenic survival of tumor cells after ionizing radiation (6 Gy). The number of DNA double-strand breaks (DSBs) in tumor cells increased with HP01 treatment, but the repair of radiation-induced DNA DSBs was not affected. Cell cycle analysis revealed that HP01, in addition to radiation, enhanced G2/M arrest in MCF-7 and HT-29 cells. Overall, HP01 not only showed a growth-inhibiting effect but also demonstrated a radiosensitizing effect on human tumor cells for the first time. We conclude that the HP01-induced G2/M accumulation of cells may be the main rationale for the drug-induced radiosensitivity. It is therefore a promising candidate for combined therapy in tumor diseases and warrants further investigation. Full article

Sulfated polysaccharides SpvF1, SpvF2, SpvF3, and SpvF4 from the brown alga S. vietnamense collected north of Hon Do (Nha Trang Bay, Vietnam) were isolated and studied. The structure of the obtained polysaccharide was studied using chemical methods and NMR spectroscopy. Fucoidans were low-sulfated (SpvF1, SpvF2) and medium-sulfated (SpvF3, SpvF4) heterogeneous polysaccharides. The molecular weight of the polysaccharides obtained was in the range of 16 to 44 kDa. All investigated fucoidans until 400 µg/mL were not cytotoxic for human colon carcinoma cells DLD-1, HCT-116, and HT-29 in vitro. Fucoidans SpvF1 and SpvF2 have inhibited the colony formation and growth of investigated cells from 20 to 30%. Fucoidans SpvF3 and SpvF4 have the strongest inhibitory effect for investigated cancer cells: from 40 to 50%. Full article

In recent years, new sources of secondary metabolites (SMs) in medicinal plants have been identified, and the introduction of these plants into field conditions has been carried out to obtain chemically diverse standardized raw material (RM). An example is mountain arnica Arnica montana L., one of Europe’s endemic endangered medicinal plant species, commonly used in pharmacy, cosmetics, and medicine. Its inflorescences (Arnicae flos) are characterized by anti-inflammatory, antiradical, antioxidant, antibacterial, antifungal, and antitumor properties. The main goals of the present research included: (i) characterization of the chemical composition of the inflorescences of A. montana harvested in different development stages; and (ii) presentation of the role of the development stage and different extraction methods in the antitumor activity of extracts through analyses of apoptosis, autophagy, and necrosis induction in human cervical carcinoma HeLa, human colon carcinoma HT29, and human colon metastatic carcinoma SW620 cell lines. The development stage was found to modify the composition of pharmacologically active substances, e.g., sesquiterpene lactones (SLs), flavonoids (Fs), and essential oil (EO), in arnica inflorescences. The content of Fs and EO increased during flowering to the full flowering phase; however, the highest content of SLs was noted in the full flowering phase and at the end of flowering. More promising results, i.e., a relatively high level of apoptosis and a low level of necrosis induced by the arnica extracts, were demonstrated in the HeLa cell line (full flowering; concentration: 0.5 µL/mL), the HT29 cell line (beginning of flowering; concentration: 0.5 µL/mL), and the SW620 cell line (stage of yellow buds; concentration: 1 µL/mL). This extremely valuable medicinal plant species provides a very broad range of RMs (e.g., inflorescences, rhizomes, roots, achenes, and all plant); therefore, attention should be paid to the more frequent use of water as a solvent in studies on the biological activity of mountain arnica extracts. Full article

This study aims to investigate the effects of kimchi made with organic ingredients and lactic acid bacteria (LAB) as starters (Leuconostoc mesenteroides + Lactiplantibacillus plantarum) on HT-29 human colon carcinoma cells. Four types of kimchi (standard kimchi (SK), commercial kimchi (CK), anticancer kimchi (AK), and organic anticancer kimchi (OAK)) were evaluated. The results show that, among the different types of kimchi studied, OAK presents high DPPH free-radical scavenging activity and total phenol and flavonoid contents, and the MTT assay shows that the growth inhibition rate against HT-29 cancer cells is the highest. In addition, the quantitative reverse transcription polymerase chain reaction (RT-qPCR) results show that, compared to SK and CK, AK and OAK can effectively down-regulate the mRNA expression of anti-apoptotic gene Bcl-2 and up-regulate the mRNA expression of the cell cycle arrest genes p21 and p53; pro-apoptotic genes Bim, Bak, and Bad; and genes for caspases 3 9. Subsequently, a Western blot test confirmed that the expression of Bcl-2 decreased and the expressions of p53, Bax, and caspases 3 and 9 increased in OAK. The abovementioned results indicate that the anticancer kimchi prepared with organic ingredients and starters of lactic acid bacteria effectively present the best antioxidant activity and inhibit the proliferation of HT-29 cancer cells by promoting apoptosis and cell cycle arrest. Full article

Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis that can lead to MSI-H cancer progression in PSC/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC. Full article

Fibrates are widely used hypolipidaemic agents that act as ligands of the peroxisome proliferator-activated receptor α (PPARα). p38 is a protein kinase that is mainly activated by environmental and genotoxic stress. We investigated the effect of the PPARα activators fenofibrate and WY-14643 and the PPARα inhibitor GW6471 on the levels of activated p38 (p-p38) in the colorectal cancer cell lines HT-29 and Caco2 in relation to their differentiation status. Fibrates increased p-p38 in undifferentiated HT-29 cells, whereas in other cases p-p38 expression was decreased. HT-29 cells showed p-p38 predominantly in the cytoplasm, whereas Caco2 cells showed higher nuclear positivity. The effect of fibrates may depend on the differentiation status of the cell, as differentiated HT-29 and undifferentiated Caco2 cells share similar characteristics in terms of villin, CYP2J2, and soluble epoxide hydrolase (sEH) expression. In human colorectal carcinoma, higher levels of p-p38 were detected in the cytoplasm, whereas in normal colonic surface epithelium, p-p38 showed nuclear positivity. The decrease in p-p38 positivity was associated with a decrease in sEH, consistent with in vitro results. In conclusion, fibrates affect the level of p-p38, but its exact role in the process of carcinogenesis remains unclear and further research is needed in this area. Full article

Probiotic strains such as Lactobacillus spp. are already known for their beneficial effect on human health and new research supports their role in colon cancer prevention and treatment. The current study reports the effect of different concentrations of Lacticaseibacillus rhamnosus (LGG, 10⁶–10⁹ CFU/mL), alone or in association with 5-fluorouracil (5-FU, 10 μM), tested against normal HaCaT cells, HT-29 colorectal adenocarcinoma and HCT-116 colorectal carcinoma cell lines. The underlying cytotoxic effect was further investigated. LGG treatment of HT-29 and HCT-116 cells caused a variety of apoptotic-related nuclear morphological changes, as revealed by DAPI staining. ELISA studies showed that LGG treatment increased caspase-3 activity and pro-apoptotic BAX protein levels while decreasing anti-apoptotic Bcl-2 protein levels and the proto-oncogene Cyclin D1. A more detailed examination of the mitochondrial function revealed that high concentrations of LGG can impair mitochondrial function in HT-29 and HCT-116 cancer cells. All of these findings suggest that LGG has a pro-apoptotic, mitochondrial-targeted, cytotoxic effect on both colon cancer cell lines studied. Full article

Fruit and leaf cuticular waxes are valuable source materials for the isolation of triterpenoids that can be applied as natural antioxidants and anticancer agents. The present study aimed at the semi-preparative fractionation of triterpenoids from cuticular wax extracts of Vaccinium vitis-idaea L. (lingonberry) leaves and fruits and the evaluation of their cytotoxic potential. Qualitative and quantitative characterization of obtained extracts and triterpenoid fractions was performed using HPLC-PDA method, followed by complementary analysis by GC-MS. For each fraction, cytotoxic activities towards the human colon adenocarcinoma cell line (HT-29), malignant melanoma cell line (IGR39), clear renal carcinoma cell line (CaKi-1), and normal endothelial cells (EC) were determined using MTT assay. Furthermore, the effect of the most promising samples on cancer spheroid growth and viability was examined. This study allowed us to confirm that particular triterpenoid mixtures from lingonberry waxes may possess stronger cytotoxic activities than crude unpurified extracts. Fractions containing triterpenoid acids plus fernenol, complexes of oleanolic:ursolic acids, and erythrodiol:uvaol were found to be the most potent therapeutic candidates in the management of cancer diseases. The specificity of cuticular wax extracts of lingonberry leaves and fruits, leading to different purity and anticancer potential of obtained counterpart fractions, was also enclosed. These findings contribute to the profitable utilization of lingonberry cuticular waxes and provide considerable insights into the anticancer effects of particular triterpenoids and pharmacological interactions. Full article

Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells. Full article

Carpesium divaricatum Sieb. & Zucc. is a plant species rich in terpenoids of anti-inflammatory and cytotoxic activity, especially germacranolides of potential medicinal value. The present study describes in vitro multiplication of C. divaricatum, analysis of active constituents in the multiple shoots, and assessment of cytotoxic activities of extracts prepared from in vitro- and field-grown plants. The plant extracts were evaluated for cytotoxicity using two melanoma cell lines (HTB140 and A375); human keratinocytes (HaCaT); two colon cancer cell lines (Caco2 and HT29); human hepatocellular carcinoma cells (HepG2); two lines of prostate cancer cells (DU145 and PC3) and prostate epithelial cells (PNT2). Chemical compositions of the assayed extracts were analyzed by HPLC/DAD, in reference to isolated compounds. Maximum of 4.07 ± 1.61 shoots regenerated from a nodal explant of C. divaricatum, cultivated in a liquid MS medium supplemented with thidiazuron (1 μM). In vitro grown shoots and plantlets of C. divaricatum accumulated terpenoids that are known as active constituents of the intact plant. Cytotoxic activity of the extracts prepared from the in vitro cultured plants was like that demonstrated by the extracts prepared from field-grown plants and seemed to be more selective than cytotoxicities of the individual germacranolides. Full article

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC₅₀) of 58.4 µM, exceeding the activity of fluorouracil (CC₅₀ = 381.2 μM) and equaling the activity of cisplatin (CC₅₀ = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer. Full article

Artemisia verlotiorum Lamotte is recognized medicinally given its long-standing ethnopharmacological uses in different parts of the world. Nonetheless, the pharmacological properties of the leaves of the plant have been poorly studied by the scientific community. Hence, this study aimed to decipher the phytochemicals; quantify through HPLC-ESI-MS analysis the plant’s biosynthesis; and evaluate the antioxidant, anti-tyrosinase, amylase, glucosidase, cholinesterase, and cytotoxicity potential on normal (NIH 3T3) and human liver and human colon cancer (HepG2 and HT 29) cell lines of this plant species. The aqueous extract contained the highest content of phenolics and phenolic acid, methanol extracted the most flavonoid, and the most flavonol was extracted by ethyl acetate. The one-way ANOVA results demonstrated that all results obtained were statistically significant at p < 0.05. A total of 25 phytoconstituents were identified from the different extracts, with phenolic acids and flavonoids being the main metabolites. The highest antioxidant potential was recorded for the aqueous extract. The best anti-tyrosinase extract was the methanolic extract. The ethyl acetate extract of A. verlotiorum had the highest flavonol content and hence was most active against the cholinesterase enzymes. The ethyl acetate extract was the best α-glucosidase and α-amylase inhibitor. The samples of Artemisia verlotiorum Lamotte in both aqueous and methanolic extracts were found to be non-toxic after 48 h against NIH 3T3 cells. In HepG2 cells, the methanolic extract was nontoxic up to 125 µg/mL, and an IC₅₀ value of 722.39 µg/mL was recorded. The IC₅₀ value exhibited in methanolic extraction of A. verlotiorum was 792.91 µg/mL in HT29 cells. Methanolic extraction is capable of inducing cell cytotoxicity in human hepatocellular carcinoma without damaging normal cells. Hence, A. verlotiorum can be recommended for further evaluation of its phytochemical and medicinal properties. Full article