Neoadjuvant treatment for colon cancer, unlike rectal cancer, is rarely used. Its position in the treatment algorithm is not precisely defined. This treatment should be considered for locally significantly advanced tumors (cT4) with extensive nodal involvement. The neoadjuvant treatment plan should be determined in a multidisciplinary team setting. We describe the main clinical trials focused on neoadjuvant chemotherapy in colon cancer. A special subgroup is dMMR/MSI-high tumors, patients with such cancers are candidates for immunotherapy treatment. Immunotherapy can induce complete remission, but can also be accompanied by long-term or permanent toxicity of the treat-ment. Neoadjuvant immunotherapy of non-metastatic colon cancer is the subject of a number of clinical trials. Currently, no immunotherapy is registered in the EU for the neoadjuvant treatment of early colon cancer.

• Klíčová slova
• colon cancer, early stage, neoadjuvant therapy, neoadjuvant treatment,
• MeSH
• adjuvantní chemoterapie MeSH
• imunoterapie MeSH
• lidé MeSH
• nádory tračníku * terapie   patologie   farmakoterapie   MeSH
• neoadjuvantní terapie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Chemoresistance represents a major issue affecting cancer therapy efficacy. Because microRNAs (miRNAs) regulate gene expression on multiple levels, their role in chemoresistance development is reasonably certain. In our previous study, miR-122-5p and miR-142-5p were identified as diagnostic, prognostic, and predictive biomarkers for primary and metastatic rectal cancer. The aim of the present study was to investigate whether these miRNAs can also reflect the disease course of patients with colon cancer (CC). Further, we focused on a deeper understanding of their involvement in 5-fluorouracil (5-FU) chemoresistance development.

• Klíčová slova
• MicroRNA, biomarker, chemoresistance, colon cancer, liquid biopsy,
• MeSH
• chemorezistence * genetika   MeSH
• fluoruracil terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA * krev   genetika   MeSH
• nádorové biomarkery krev   genetika   MeSH
• nádory tračníku * farmakoterapie   genetika   krev   patologie   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fluoruracil MeSH
• mikro RNA * MeSH
• MIRN122 microRNA, human MeSH Prohlížeč
• MIRN142 microRNA, human MeSH Prohlížeč
• nádorové biomarkery MeSH

Platinum(IV) compounds possess distinct properties that set them apart from platinum(II) compounds. Often designed as prodrugs, they are reduced within cancer cells to their active platinum(II) form, enabling their cytotoxic effects. Their versatility also lies in their ability to be functionalized and conjugated with bioactive molecules to enhance cancer cell targeting. This report introduces new prodrugs that combine antitumor cisplatin with axially coordinated eugenol, leveraging their synergistic action to target cancer stem cells. A third bioactive ligand, 4-phenylbutyrate or octanoate, was added to further enhance biological activity, creating 'triple action' prodrugs. These new platinum(IV) prodrugs offer a novel approach to cancer therapy by improving targeting, increasing efficacy, overcoming drug resistance, and reducing tumor invasiveness while sparing healthy tissue.

• Klíčová slova
• Cancer stem cells, Cisplatin, Eugenol, Platinum(IV), Spheroids,
• MeSH
• cisplatina * farmakologie   MeSH
• eugenol * farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * účinky léků   patologie   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• prekurzory léčiv * farmakologie   chemie   MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina * MeSH
• eugenol * MeSH
• prekurzory léčiv * MeSH
• protinádorové látky * MeSH

Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C∧N)(phen)2]+, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.

• MeSH
• apoptóza účinky léků   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• chinoxaliny * chemie   farmakologie   chemická syntéza   MeSH
• fotochemoterapie * MeSH
• fotosenzibilizující látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * účinky léků   patologie   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium * chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chinoxaliny * MeSH
• fotosenzibilizující látky * MeSH
• komplexní sloučeniny * MeSH
• protinádorové látky * MeSH
• reaktivní formy kyslíku MeSH
• ruthenium * MeSH

Inhibition of soluble epoxide hydrolase (sEH) appears to be promising for the treatment of many diseases. Studies have focused on the beneficial effects of epoxyeicosatrienoic acids (EETs), which are sEH substrates. However, our recent studies have shown that the sEH activity is crucial for the proper intestinal cell differentiation. In this recent study, we investigated the impact of TPPU, an inhibitor of sEH, on the colon cancer cell lines Caco2 and HT-29. We analysed the changes in the expression of the cytoskeletal protein ezrin and the phosphorylated protein kinase p38 (p-p38). Our results showed a decrease in ezrin expression in differentiated cells and an increase in p-p38 expression after TPPU treatment. Immunocytochemical staining revealed a higher staining intensity of p-p38 in the nuclei of HT-29 cells following TPPU treatment. Immunohistochemical staining was performed on human samples of normal colon tissue, grade 2 tumours, and embryonal/foetal tissues. The staining intensity of ezrin in tumours was reduced in the surface area compared to the crypts. Additionally, we observed the translocation of p-p38 expression from the cytoplasm to the nucleus during differentiation. The tumour samples exhibited higher levels of p-p38 in the cytoplasm, similar to normal undifferentiated tissue. To observe the disruption of the cytoskeleton after TPPU treatment, confocal microscopy was used. It was found that β-actin associated with ezrin forms clusters under the plasma membranes. All of these results are significant because sEH inhibitors are being tested in clinical trials, but they could cause an unexpected adverse effects.

• Klíčová slova
• Ezrin, Immunohistochemistry, Intestinal Epithelium, P-p38, Soluble Epoxide Hydrolase, TPPU,
• MeSH
• buněčná diferenciace * účinky léků   MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• cytoskeletální proteiny * metabolismus   MeSH
• epoxid hydrolasy * antagonisté a inhibitory   metabolismus   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytoskeletální proteiny * MeSH
• epoxid hydrolasy * MeSH
• ezrin MeSH Prohlížeč
• fenylmočovinové sloučeniny MeSH
• inhibitory enzymů MeSH
• mitogenem aktivované proteinkinasy p38 MeSH

Hyaluronic acid (HA) coated irinotecan loaded lignin nanoparticles (HDLNPs) were synthesized using ionic interaction method. Optimized nanoparticles were characterized for their active chemotherapeutic targeting potential to CD44 receptors overly-expressed on cancer cells. Blood component interaction studies supported hemocompatible nature of HDLNPs and also demonstrated their sustained plasma residence property. Cell anti-proliferation and mitochondrial depolarization studies on HT-29 cells suggest significantly (p < 0.01) improved chemotherapeutic efficacy of HDLNPs. In vitro cell based studies showed that nanoparticles have retained antioxidant activity of lignin that can prevent cancer relapse. In vivo biodistribution studies in tumor-bearing Balb/c mice confirmed improved drug localization in tumor site for longer duration. Tumor regression and histopathological studies indicated the efficacy ofligand-assisted targeting chemotherapy over the conventional therapy. Hematological and biochemical estimation suggested that irinotecan-associated myelosuppression, liver steatosis and rare kidney failure can be avoided by its encapsulation in HA-coated lignin nanoparticles. HDLNPs were found to be stable over a period of 12 months.

• Klíčová slova
• Active targeting, Hyaluronic acid, Lignin nanoparticles, Mitochondrial depolarization, Solid tumor, hyaluronan/CD44 receptors,
• MeSH
• antigeny CD44 metabolismus   MeSH
• irinotekan farmakologie   MeSH
• kyselina hyaluronová chemie   MeSH
• lignin MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku * farmakoterapie   MeSH
• nanočástice * chemie   MeSH
• protinádorové látky * chemie   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD44 MeSH
• irinotekan MeSH
• kyselina hyaluronová MeSH
• lignin MeSH
• protinádorové látky * MeSH

Colorectal cancer (CRC) is one of the most deaths causing diseases worldwide. Several risk factors including hormones like insulin and insulin like growth factors (e.g., IGF-1) have been considered responsible for growth and progression of colon cancer. Though there is a huge advancement in the available screening as well as treatment techniques for CRC. There is no significant decrease in the mortality of cancer patients. Moreover, the current treatment approaches for CRC are associated with serious challenges like drug resistance and cancer re-growth. Given the severity of the disease, there is an urgent need for novel therapeutic agents with ideal characteristics. Several pieces of evidence suggested that natural products, specifically medicinal plants, and derived phytochemicals may serve as potential sources for novel drug discovery for various diseases including cancer. On the other hand, cancer cells like colon cancer require a high basal level of reactive oxygen species (ROS) to maintain its own cellular functions. However, excess production of intracellular ROS leads to cancer cell death via disturbing cellular redox homeostasis. Therefore, medicinal plants and derived phytocompounds that can enhance the intracellular ROS and induce apoptotic cell death in cancer cells via modulating various molecular targets including IGF-1 could be potential therapeutic agents. Alkaloids form a major class of such phytoconstituents that can play a key role in cancer prevention. Moreover, several preclinical and clinical studies have also evidenced that these compounds show potent anti-colon cancer effects and exhibit negligible toxicity towards the normal cells. Hence, the present evidence-based study aimed to provide an update on various alkaloids that have been reported to induce ROS-mediated apoptosis in colon cancer cells via targeting various cellular components including hormones and growth factors, which play a role in metastasis, angiogenesis, proliferation, and invasion. This study also provides an individual account on each such alkaloid that underwent clinical trials either alone or in combination with other clinical drugs. In addition, various classes of phytochemicals that induce ROS-mediated cell death in different kinds of cancers including colon cancer are discussed.

• Klíčová slova
• HIF-1α, IGF-1, IGFBP-3, alkaloids, apoptosis, colon cancer progression, mutation, oxidative stress,
• MeSH
• alkaloidy * terapeutické užití   MeSH
• hormony terapeutické užití   MeSH
• insulinu podobný růstový faktor I MeSH
• lidé MeSH
• nádory tračníku * farmakoterapie   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• alkaloidy * MeSH
• hormony MeSH
• insulinu podobný růstový faktor I MeSH
• reaktivní formy kyslíku MeSH

Self-assembled enantiomers of an asymmetric di-iron metallohelix differ in their antiproliferative activities against HCT116 colon cancer cells such that the compound with Λ-helicity at the metals becomes more potent than the Δ compound with increasing exposure time. From concentration- and temperature-dependent 57Fe isotopic labelling studies of cellular accumulation we postulate that while the more potent Λ enantiomer undergoes carrier-mediated efflux, for Δ the process is principally equilibrative. Cell fractionation studies demonstrate that both enantiomers localise in a similar fashion; compound is observed mostly within the cytoskeleton and/or genomic DNA, with significant amounts also found in the nucleus and membrane, but with negligible concentration in the cytosol. Cell cycle analyses using flow cytometry reveal that the Δ enantiomer induces mild arrest in the G1 phase, while Λ causes a very large dose-dependent increase in the G2/M population at a concentration significantly below the relevant IC50. Correspondingly, G2-M checkpoint failure as a result of Λ-metallohelix binding to DNA is shown to be feasible by linear dichroism studies, which indicate, in contrast to the Δ compound, a quite specific mode of binding, probably in the major groove. Further, spindle assembly checkpoint (SAC) failure, which could also be responsible for the observed G2/M arrest, is established as a feasible mechanism for the Λ helix via drug combination (synergy) studies and the discovery of tubulin and actin inhibition. Here, while the Λ compound stabilizes F-actin and induces a distinct change in tubulin architecture of HCT116 cells, Δ promotes depolymerization and more subtle changes in microtubule and actin networks.

• MeSH
• aktiny MeSH
• DNA chemie   MeSH
• lidé MeSH
• mikrotubuly MeSH
• nádory tračníku * farmakoterapie   MeSH
• tubulin * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aktiny MeSH
• DNA MeSH
• tubulin * MeSH

An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon cancer. Numerous Akt-targeted therapies are being developed, the activity of Akt-inhibitors is, however, strongly pH-dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt inhibitor perifosine and the Bcl-2/Bcl-xL inhibitor ABT-737 was tested in colon cancer HT-29 and HCT-116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour-specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon cancer.

• Klíčová slova
• ABT-737, colon cancer, combined treatment, peeling analysis, perifosine, spheroids, synergism, tumour microenvironment,
• MeSH
• apoptóza MeSH
• fosfatidylinositol-3-kinasy MeSH
• fosforylcholin * analogy a deriváty   farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie účinky léků   MeSH
• nádorové mikroprostředí MeSH
• nádory tračníku * farmakoterapie   MeSH
• protinádorové látky * farmakologie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• synergismus léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABT-737 MeSH Prohlížeč
• fosfatidylinositol-3-kinasy MeSH
• fosforylcholin * MeSH
• inhibitory proteinkinas MeSH
• perifosine MeSH Prohlížeč
• protinádorové látky * MeSH
• protoonkogenní proteiny c-akt MeSH

Three-dimensional cell culture systems are increasingly used for biological and anticancer drug screening as they mimic the structure and microenvironment of tumors more closely than conventional two-dimensional cell models. In this study, the growth kinetics of colon adenocarcinoma-derived spheroids (HT-29 cell line) cultivated in liquid marble micro-bioreactors and nonadherent PDMS-coated well plates was investigated in detail and enabled precise control of the spheroid size by the seed cell density and cultivation time. The therapeutic effect of 5-fluorouracil and irinotecan hydrochloride in 2D monolayer cell culture and 3D tumor spheroids revealed an unexpected twist in their efficacy due to different ability to penetrate through 3D microtissue. For 5-fluorouracil, the inhibitory concentration IC50 after 48 h exposure increased from 11.3 µM for a 2D cell culture to 707.7 µM for a 3D spheroid. In the case of irinotecan, IC50 increased from 24.9 µM to 77.8 µM. Despite its higher molar weight, irinotecan appeared to penetrate the 3D spheroid structure more efficiently than 5-fluorouracil. While 5-fluorouracil mainly caused a suppression of spheroid growth from the outside, irinotecan affected the entire spheroid and caused its originally compact structure to disintegrate. The acquired results highlight the need to screen cancer chemotherapeutics on 3D tumor models, as contrasting results can be obtained compared to standard 2D cell cultures.

• Klíčová slova
• 3D Cell cultures, 5-Fluorouracil, Irinotecan hydrochloride, Liquid marbles, Polydimethylsiloxane, Tumor spheroids,
• MeSH
• adenokarcinom * MeSH
• buněčné sféroidy MeSH
• cytostatické látky * farmakologie   MeSH
• fluoruracil farmakologie   MeSH
• irinotekan farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• nádory tračníku * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytostatické látky * MeSH
• fluoruracil MeSH
• irinotekan MeSH