A supervised machine-learning approach for the efficient development of a multi method (LC-MS) for a large number of drugs and subsets thereof: focus on oral antitumor agents.

OBJECTIVES: Accumulating evidence argues for a more widespread use of therapeutic drug monitoring (TDM) to support individualized medicine, especially for therapies where toxicity and efficacy are critical issues, such as in oncology. However, development of TDM assays struggles to keep pace with the rapid introduction of new drugs. Therefore, novel approaches for faster assay development are needed that also allow effortless inclusion of newly approved drugs as well as customization to smaller subsets if scientific or clinical situations require. METHODS: We applied and evaluated two machine-learning approaches i.e., a regression-based approach and an artificial neural network (ANN) to retention time (RT) prediction for efficient development of a liquid chromatography mass spectrometry (LC-MS) method quantifying 73 oral antitumor drugs (OADs) and five active metabolites. Individual steps included training, evaluation, comparison, and application of the superior approach to RT prediction, followed by stipulation of the optimal gradient. RESULTS: Both approaches showed excellent results for RT prediction (mean difference ± standard deviation: 2.08 % ± 9.44 % ANN; 1.78 % ± 1.93 % regression-based approach). Using the regression-based approach, the optimum gradient (4.91 % MeOH/min) was predicted with a total run time of 17.92 min. The associated method was fully validated following FDA and EMA guidelines. Exemplary modification and application of the regression-based approach to a subset of 14 uro-oncological agents resulted in a considerably shortened run time of 9.29 min. CONCLUSIONS: Using a regression-based approach, a multi drug LC-MS assay for RT prediction was efficiently developed, which can be easily expanded to newly approved OADs and customized to smaller subsets if required.

What we know on the potential use of exosomes for nanodelivery.

Antitumor therapy is taking into consideration the possibility to use natural nanovesicles, called exosomes, as an ideal delivery for both old and new anti-cancer molecules. This with the attempt to improve the efficacy, at the same time reducing the systemic toxicity of physical, chemical, and biological molecules. Exosomes may in fact increase the level of biomimetism, through simulating what really occurs in nature. Although extracellularly released vesicles include both microvesicles (MVs) and exosomes, only exosomes have the size that may be considered suitable for potential use to this purpose, also by analogy with the diffusely used artificial nanoparticles, such as lyposomes. In fact, recent reports have shown that exosomes are able to interact with target cells within an organ or at a distance using different mechanisms. Much is yet to be understood about exosomes, and currently, we are looking at the visible top of an iceberg, with most of what we have to understand on these nanovesicles still under the sea. In fact, we know that exosomes released by normal cells always trigger positive effects, while those released by cells in pathological condition, such as tumors may induce undesired, dangerous, and mostly unknown effects. To date we have many pre-clinical data available and possibly useful to think about a strategic use of exosomes as a delivery nanodevice in cancer treatment. However, this review wants to critically emphasize two important points actually hampering further discussion in the field : (i) the clinical data are virtually absent at the moment ; (ii) the best cellular source of exosomes to be used to deliver drugs is really far to be defined. Facing off these two points may well facilitate the attempt to figure out this very important issue for improving at the best future anti-cancer treatments.

The application of zebrafish patient-derived xenograft tumor models in the development of antitumor agents.

The cost of antitumor drug development is enormous, yet the clinical outcomes are less than satisfactory. Therefore, it is of great importance to develop effective drug screening methods that enable accurate, rapid, and high-throughput discovery of lead compounds in the process of preclinical antitumor drug research. An effective solution is to use the patient-derived xenograft (PDX) tumor animal models, which are applicable for the elucidation of tumor pathogenesis and the preclinical testing of novel antitumor compounds. As a promising screening model organism, zebrafish has been widely applied in the construction of the PDX tumor model and the discovery of antineoplastic agents. Herein, we systematically survey the recent cutting-edge advances in zebrafish PDX models (zPDX) for studies of pathogenesis mechanisms and drug screening. In addition, the techniques used in the construction of zPDX are summarized. The advantages and limitations of the zPDX are also discussed in detail. Finally, the prospects of zPDX in drug discovery, translational medicine, and clinical precision medicine treatment are well presented.

Dual drug loaded polypeptide delivery systems for cancer therapy.

The present study was aimed to prepare and examine in vitro novel dual-drug loaded delivery systems. Biodegradable nanoparticles based on poly(L-glutamic acid-co-D-phenylalanine) were used as nanocarriers for encapsulation of two drugs from the paclitaxel, irinotecan, and doxorubicin series. The developed delivery systems were characterised with hydrodynamic diameters less than 300 nm (PDI < 0.3). High encapsulation efficiencies (≥75%) were achieved for all single- and dual-drug formulations. The release studies showed faster release at acidic pH, with the release rate decreasing over time. The release patterns of the co-encapsulated forms of substances differed from those of the separately encapsulated drugs, suggesting differences in drug-polymer interactions. The joint action of encapsulated drugs was analysed using the colon cancer cells, both for the dual-drug delivery sytems and a mixture of single-drug formulations. The encapsulated forms of the drug combinations demonstrated comparable efficacy to the free forms, with the encapsulation enhancing solubility of the hydrophobic drug paclitaxel.

Dual-Stimuli-Sensitive Smart Hydrogels Containing Magnetic Nanoparticles as Antitumor Local Drug Delivery Systems-Synthesis and Characterization.

The aim of this study was to develop an innovative, dual-stimuli-responsive smart hydrogel local drug delivery system (LDDS), potentially useful as an injectable simultaneous chemotherapy and magnetic hyperthermia (MHT) antitumor treatment device. The hydrogels were based on a biocompatible and biodegradable poly(ε-caprolactone-co-rac-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-rac-lactide) (PCLA-PEG-PCLA, PCLA) triblock copolymer, synthesized via ring-opening polymerization (ROP) in the presence of a zirconium(IV) acetylacetonate (Zr(acac)4) catalyst. The PCLA copolymers were successfully synthesized and characterized using NMR and GPC techniques. Furthermore, the gel-forming and rheological properties of the resulting hydrogels were thoroughly investigated, and the optimal synthesis conditions were determined. The coprecipitation method was applied to create magnetic iron oxide nanoparticles (MIONs) with a low diameter and a narrow size distribution. The magnetic properties of the MIONs were close to superparamagnetic upon TEM, DLS, and VSM analysis. The particle suspension placed in an alternating magnetic field (AMF) of the appropriate parameters showed a rapid increase in temperature to the values desired for hyperthermia. The MIONs/hydrogel matrices were evaluated for paclitaxel (PTX) release in vitro. The release was prolonged and well controlled, displaying close to zero-order kinetics; the drug release mechanism was found to be anomalous. Furthermore, it was found that the simulated hyperthermia conditions had no effect on the release kinetics. As a result, the synthesized smart hydrogels were discovered to be a promising antitumor LDDS, allowing simultaneous chemotherapy and hyperthermia treatment.

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations.

In this work, we elucidated some key aspects of the mechanism of action of the cisplatin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5'-(2'-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2-3. The affinities of cisplatin metabolites 2-3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2-3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study's insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated.

Novel nanomedicines to overcome cancer multidrug resistance.

Chemotherapy remains a powerful tool to eliminate malignant cells. However, the efficacy of chemotherapy is compromised by the frequent emergence of intrinsic and acquired multidrug resistance (MDR). These chemoresistance modalities are based on a multiplicity of molecular mechanisms of drug resistance, including : 1) Impaired drug uptake into cancer cells; 2) Increased expression of ATP-binding cassette efflux transporters; 3) Loss of function of pro-apoptotic factors; 4) Enhanced DNA repair capacity; 5) Qualitative or quantitative alterations of specific cellular targets; 6) Alterations that allow cancer cells to tolerate adverse or stressful conditions; 7) Increased biotransformation or metabolism of anticancer drugs to less active or completely inactive metabolites; and 8) Intracellular and intercellular drug sequestration in well-defined organelles away from the cellular target. Hence, one of the major aims of cancer research is to develop novel strategies to overcome cancer drug resistance. Over the last decades, nanomedicine, which focuses on targeted delivery of therapeutic drugs into tumor tissues using nano-sized formulations, has emerged as a promising tool for cancer treatment. Therefore, nanomedicine has been introduced as a reliable approach to improve treatment efficacy and minimize detrimental adverse effects as well as overcome cancer drug resistance. With rationally designed strategies including passively targeted delivery, actively targeted delivery, delivery of multidrug combinations, as well as multimodal combination therapy, nanomedicine paves the way towards efficacious cancer treatment and hold great promise in overcoming cancer drug resistance. Herein, we review the recent progress of nanomaterials used in medicine, including liposomal nanoparticles, polymeric nanoparticles, inorganic nanoparticles and hybrid nanoparticles, to surmount cancer multidrug resistance. Finally, the future perspectives of the application of nanomedicine to reverse cancer drug resistance will be addressed.

Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration.

Kiteplatin, [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl2(OBz)2(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·106 LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.

Nivolumab monotherapy or combination therapy with ipilimumab for lung cancer: a systemic review and meta-analysis.

BACKGROUND: The high incidence and mortality of lung cancer have seriously affected human life and health. Nivolumab is a monoclonal antibody that can inhibit programmed death 1 (PD-1) and Ipilimumab is a monoclonal antibody against CTLA-4(cytotoxic T lymphocyte-associated antigen 4), both of which can prevent the immune escape of tumor cells. Our goal was to synthesize evidence from published randomized controlled trials involving the safety and efficacy of either Nivolumab alone or in combination for the treatment of unresectable lung cancer. METHODS: We searched the following electronic databases: PubMed, Embase, and Cochrane libraries, and screened the retrieved records for eligibility. We used the Stata16 software for the analyses. The results of the analysis are expressed as hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% confidence intervals (CI). RESULTS: The final analysis included seven trials involving 3817 patients. Among patients with advanced lung cancer, patients using immunotherapy had better overall survival (OS), progression-free survival (PFS), and an objective response rate (ORR) than patients receiving chemotherapy. The HR of Nivolumab monotherapy or combination therapy with OS was compared with that of chemotherapy (HR: 0.73, 95% CI 0.64-0.83; HR: 0.67, 95% CI 0.55-0.81), and the HR of PFS was (HR: 0.81, 95% CI 0.69-0.94; HR: 0.67, 95% CI 0.55-0.82). CONCLUSIONS: Immunotherapy has been shown to have more clinically meaningful survival benefits for patients with lung cancer, whether monotherapy or combination immunotherapy. CRD42020213440.

To betray or to fight? The dual identity of the mitochondria in cancer.

Mitochondria are highly dynamic organelles that provide energy for oxidative phosphorylation in cells. Equally, they are the major sites for the metabolism of amino acids, lipids and iron. When cells become cancerous, the morphology, cellular location and metabolic mode of the mitochondria change accordingly. These mitochondrial changes can have two opposing effects on cancer: procancer and anticancer effects. Specifically, mitochondria play roles in the fight against cancer by participating in processes such as ferroptosis, mitophagy and antitumor immunity. Contrastingly, cancer cells can also enslave mitochondria to give them the conditions necessary for growth and metastasis. Moreover, through mitochondria, cancer cells can escape from immune surveillance, resulting in their immune escape and enhanced malignant transformation ability. At present, cancer-related studies of mitochondria are one-sided; therefore, we aim to provide a comprehensive understanding by systematically reviewing the two-sided cancer-related properties of mitochondria. Mitochondrial-targeted drugs are gradually emerging and showing significant advantages in cancer treatment; thus, our in-depth exploration of mitochondria in cancer will help to provide theoretical support for the future provision of efficient and low-toxicity cancer treatments.

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity.

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5'-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5'-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells' death by apoptosis and necrosis.

The Influence of Antitumor Unsymmetrical Bisacridines on 3D Cancer Spheroids Growth and Viability.

The culture of 3D spheroids is a promising tool in drug development and testing. Recently, we synthesized a new group of compounds, unsymmetrical bisacridines (UAs), which exhibit high cytotoxicity against various human cell lines and antitumor potency against several xenografts. Here, we describe the ability of four UAs-C-2028, C-2041, C-2045, and C-2053-to influence the growth of HCT116 and H460 spheres and the viability of HCT116 cells in 3D culture compared with that in 2D standard monolayer culture. Spheroids were generated using ultra-low-attachment plates. The morphology and diameters of the obtained spheroids and those treated with UAs were observed and measured under the microscope. The viability of cells exposed to UAs at different concentrations and for different incubation times in 2D and 3D cultures was assessed using 7-AAD staining. All UAs managed to significantly inhibit the growth of HCT116 and H460 spheroids. C-2045 and C-2053 caused the death of the largest population of HCT116 spheroid cells. Although C-2041 seemed to be the most effective in the 2D monolayer experiments, in 3D conditions, it turned out to be the weakest compound. The 3D spheroid culture seems to be a suitable method to examine the efficiency of new antitumor compounds, such as unsymmetrical bisacridines.

Bile acids as novel enhancers of CNS targeting antitumor drugs: a comprehensive review.

Despite a relatively low prevalence of primary brain tumors, they continuously attract scientific interest because of the complexity of their treatment due to their location behind the blood-brain barrier. The main challenge in treatment of brain tumors is not the efficacy of the drugs, per se, but the low efficiency of drug delivery to malignant cells. At the core of the problem is the complex structure of the blood-brain barrier. Nowadays, there is evidence supporting the claim that bile acids have the ability to cross the blood-brain barrier. That ability can be exploited by taking a part in novel drug carrier designs. Bile acids represent a drug carrier system as a part of a mixed micelle composition, bilosomes and conjugates with various drugs. This review discusses the current knowledge related to bile acid molecules as drug penetration modifying agents, with the focus on central nervous system antitumor drug delivery.

A systematic review of the budget impact analyses for antitumor drugs of lung cancer.

BACKGROUND: Budget impact analyses (BIAs) are used for reimbursement decisions and drug access medical insurance, as a supplement to cost-effectiveness analyses (CEAs). OBJECTIVES: We systematically reviewed BIAs for antitumor drugs of lung cancer to provide reference for high-value drug budget impact analyses and decision making. METHODS: We conducted a literature search on PubMed, EMbase, The Cochrane Library, China National Knowledge Infrastructure and Wanfang Data Knowledge Service Platform from 2010 to 2019. The methodological indicators and result information of the budget impact analyses were extracted and evaluated for quality. RESULTS: A total of 14 studies on the budget impact for antitumor drugs of lung cancer were included, and the overall quality was good. Half of studies were from developed countries. Nine of the studies were designed using the BIA cost calculation model, and two were simulated using the Markov model Monte Carlo model. From all studies, only 14.3% reported model validation. The budget impact results of the same drug in different countries were inconsistent. CONCLUSIONS: Included studies evaluating budget impact analyses for anti-tumor drugs of lung cancer showed variability in the methodological framework for BIAs. The budget impact analyses of high-value drugs need to be more stringent to ensure the accuracy of the parameters, and should provide reliable results based on real data to decision-making departments, which should carefully consider access to lung cancer drugs.

Nanomechanics in Monitoring the Effectiveness of Drugs Targeting the Cancer Cell Cytoskeleton.

Increasing attention is devoted to the use of nanomechanics as a marker of various pathologies. Atomic force microscopy (AFM) is one of the techniques that could be applied to quantify the nanomechanical properties of living cells with a high spatial resolution. Thus, AFM offers the possibility to trace changes in the reorganization of the cytoskeleton in living cells. Impairments in the structure, organization, and functioning of two main cytoskeletal components, namely, actin filaments and microtubules, cause severe effects, leading to cell death. That is why these cytoskeletal components are targets for antitumor therapy. This review intends to describe the gathered knowledge on the capability of AFM to trace the alterations in the nanomechanical properties of living cells induced by the action of antitumor drugs that could translate into their effectiveness.

Comparative Study of Antitumor Efficiency of Intraperitoneal and Intravenous Cytostatics in Experimental Rats with Disseminated Ovarian Cancer.

Antitumor efficiencies of cytostatics dioxadet, cisplatin, mitomycin C, melphalan, and paclitaxel after a single intraperitoneal or intravenous injection in doses of 1.5, 4, 1.5, 2, and 5 mg/kg, respectively, were studied on the model of transplanted ovarian tumor in 124 rats. The antitumor effects were evaluated by the increase in median survival. Dioxadet, cisplatin, and melphalan injected intraperitoneally significantly prolonged the lifespan median - by 79, 88, and 114%, respectively, and were in fact ineffective, when injected intravenously. Intraperitoneal mitomycin C prolonged lifespan median by just 35%, intravenous - by 152%. Paclitaxel injected intraperitoneally and intravenously prolonged the lifespan median by 45 and 81%, respectively.

From Composition to Cure: A Systems Engineering Approach to Anticancer Drug Carriers.

The molecular complexity and heterogeneity of cancer has led to a persistent, and as yet unsolved, challenge to develop cures for this disease. The pharmaceutical industry focuses the bulk of its efforts on the development of new drugs, but an alternative approach is to improve the delivery of existing drugs with drug carriers that can manipulate when, where, and how a drug exerts its therapeutic effect. For the treatment of solid tumors, systemically delivered drug carriers face significant challenges that are imposed by the pathophysiological barriers that lie between their site of administration and their site of therapeutic action in the tumor. Furthermore, drug carriers face additional challenges in their translation from preclinical validation to clinical approval and adoption. Addressing this diverse network of challenges requires a systems engineering approach for the rational design of optimized carriers that have a realistic prospect for translation from the laboratory to the patient.

Oleic acid complex of bovine α-lactalbumin induces eryptosis in human and other erythrocytes by a Ca(2+)-independent mechanism.

BACKGROUND: Complexes of oleic acid (OA) with milk α-lactalbumin, received remarkable attention in view of their selective toxicity towards a spectrum of tumors during the last two decades. OA complexes of some structurally related/unrelated proteins are also tumoricidal. Erythrocytes are among the few differentiated cells that are sensitive and undergo hemolysis when exposed to the complexes. METHODS: The effects of OA complex of bovine α-lactalbumin (Bovine Alpha-lactalbumin Made LEthal to Tumor cells, BAMLET) on human, goat and chicken erythrocytes on calcein leakage, phosphatidylserine exposure, morphological changes and hemolysis were studied by confocal microscopy, FACS analysis, scanning electron microscopy and measuring hemoglobin release. RESULTS: Erythrocytes exposed to BAMLET undergo eryptosis-like alterations as revealed by calcein leakage, surface phosphatidylserine exposure and transformation to echinocytes at low concentrations and hemolysis when the concentration of the complex was raised. Ca(2+) was not essential and restricted the alterations when included in the medium. The BAMLET-induced alterations in human erythrocytes were prevented by the cation channel inhibitors, amiloride and BaCl2 but not by inhibitors of thiol proteases, sphingomyelinase and by the antioxidant N-acetyl cysteine. CONCLUSIONS: The work shows for the first time that low concentrations of BAMLET induces eryptosis in erythrocytes by a novel mechanism not requiring Ca(2+) and hemolysis by detergent-like action by the released OA at higher concentrations. GENERAL SIGNIFICANCE: The study points out to the need for a comprehensive evaluation of the toxicity of OA complexes of α-lactalbumin and other proteins towards erythrocytes and other differentiated cells before being considered for therapy.

Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position.

The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, where TSPO is much more abundant. The novel Pt(IV) complex, cis,trans,cis-[Pt(ethanedioato)Cl{2-(2-(4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenoxy)acetate)-ethanolato}(1R,2R-DACH)] (DACH = diaminocyclohexane), has been fully characterized by spectroscopic and spectrometric techniques and tested in vitro against human MCF7 breast carcinoma, U87 glioblastoma, and LoVo colon adenocarcinoma cell lines. In addition, affinity for TSPO (IC50 = 18.64 nM), cellular uptake (ca. 2 times greater than that of oxaliplatin in LoVo cancer cells, after 24 h treatment), and perturbation of cell cycle progression were investigated. Although the new compound was less active than oxaliplatin and did not exploit a synergistic proapoptotic effect due to the presence of the TSPO ligand, it appears to be promising in a receptor-mediated drug targeting context towards TSPO-overexpressing tumors, in particular colorectal cancer (IC50 = 2.31 µM after 72 h treatment).

Interaction between intestinal flora and gastric cancer in tumor microenvironment.

Gastric Cancer (GC) is a prevalent malignancy globally and is the third leading cause of cancer-related deaths. Recent researches focused on the correlation between intestinal flora and GC. Studies indicate that bacteria can influence the development of gastrointestinal tumors by releasing bacterial extracellular vesicles (BEVs). The Tumor microenvironment (TME) plays an important role in tumor survival, with the interaction between intestinal flora, BEVs, and TME directly impacting tumor progression. Moreover, recent studies have demonstrated that intestinal microflora and BEVs can modify TME to enhance the effectiveness of antitumor drugs. This review article provides an overview and comparison of the biological targets through which the intestinal microbiome regulates TME, laying the groundwork for potential applications in tumor diagnosis, treatment, and prognosis.