The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.     

Postbiotics,Metabolic Signaling,and Cancer

Postbiotics are health-promoting microbial metabolites delivered as a functional food or a food supplement. They either directly influence signaling pathways of the body or indirectly manipulate metabolism and the composition of intestinal microflora. Cancer is the second leading cause of death worldwide and even though the prognosis of patients is improving, it is still poor in the substantial part of the cases. The preventable nature of cancer and the importance of a complex multi-level approach in anticancer therapy motivate the search for novel avenues of establishing the anticancer environment in the human body. This review summarizes the principal findings demonstrating the usefulness of both natural and synthetic sources of postbotics in the prevention and therapy of cancer. Specifically, the effects of crude cell-free supernatants, the short-chain fatty acid butyrate, lactic acid, hydrogen sulfide, and β-glucans are described. Contradictory roles of postbiotics in healthy and tumor tissues are highlighted. In conclusion, the application of postbiotics is an efficient complementary strategy to combat cancer.     

Facile Synthesis of Manganese Tellurite Nanoparticles for Magnetic Resonance Imaging-Guided Photothermal Therapy

In this study, manganese tellurite (MnTeO₃) nanoparticles are developed as theranostic agents for magnetic resonance imaging (MRI)-guided photothermal therapy of tumor. MnTeO₃ nanoparticles are synthesized via a simple one-step method. The as-synthesized MnTeO₃ nanoparticles with uniform size show good biocompatibility. In particular, MnTeO₃ nanoparticles exhibit a high photothermal conversion efficiency (η = 26.3%), which is higher than that of gold nanorods. Moreover, MnTeO₃ nanoparticles also have high MRI performance. The longitudinal relaxivity (r₁) value of MnTeO₃ nanoparticles is determined to be 8.08 ± 0.2 mm ⁻¹ s⁻¹, which is higher than that of clinically approved T₁-contrast agents Gd-DTPA (4.49 ± 0.1 mm ⁻¹ s⁻¹). The subsequent MnTeO₃ nanoparticles-mediated photothermal therapy displays a highly efficient ablation of tumor cells both in vitro and in vivo with negligible toxicity. It is demonstrated that MnTeO₃ nanoparticles can serve as promising theranostic agents with great potentials for MRI-guided photothermal therapy.     

89Zr Labeled Fe3O4@TiO2 Nanoparticles: In Vitro Afffinities with Breast and Prostate Cancer Cells

In this study, Fe₃O₄@TiO₂ nanoparticles were synthesized as a new Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) hybrid imaging agent and radiolabeled with ⁸⁹Zr. In addition, Fe₃O₄ nanoparticles were synthesized and radiolabeled with ⁸⁹Zr. Df-Bz-NCS was used as bifunctional ligand. The nanoconjugates were characterized with transmission electron microscopy, scanning electron microscopy, and dynamic light scattering. Radiolabeling yields were 100%. Breast and prostate cancer cell affinities and cytotoxicity were determined using in vitro cell culture assays. The results demonstrated that Fe₃O₄@TiO₂ nanoparticles are promising for PET/MR imaging. Finally, unlike Fe₃O₄ nanoparticles, Fe₃O₄@TiO₂ nanoparticles showed a fluorescence spectrum at an excitation wavelength of 250 nm and an emission wavelength of 314 nm. Therefore, in addition to bearing the magnetic properties of Fe₃O₄ nanoparticles, Fe₃O₄@TiO₂ nanoparticles display fluorescence emission. This provides them with photodynamic therapy potential. Therefore multimodal treatment was performed with the combination of PDT and RT by using human prostate cancer cell line (PC3). The development of ⁸⁹Zr-Df-Bz-NCS-Fe₃O₄@TiO₂ nanoparticles as a new multifunctional PET/MRI agent with photodynamic therapy and hyperthermia therapeutic ability would be very useful.     

Studies of proteasome inhibition and apoptosis induction in triple‐negative breast cancer cells by novel amino acid–polypyridine–copper complex

An innovative ternary copper(II) complex, [Cu(Cl‐PIP)(Tyr)Cl]_n, has been synthesized and characterized using infrared spectroscopy, elemental analysis and single‐crystal X‐ray diffraction analysis. X‐ray crystallography indicates that the Cu atom is five‐coordinated in a square‐pyramidal configuration. The unit forms a one‐dimensional chain along the crystallographic c‐axis. The complex was screened for cytotoxicity against a panel of eight human cancer cell lines, namely MDA‐MB‐231, CAL‐51, K562, HeLa, SGC‐7901, A549, MCF‐7 and SMMC‐7721. The best anticancer activity was obtained with triple‐negative breast cancer CAL‐51 and MDA‐MB‐231 cell lines, with IC₅₀ values in the range 0.035–0.10 μM, and this was better than using carboplatin. The complex inhibits proteasomal chymotrypsin‐like activity, and docking studies reveal its interaction with 20S proteasome. In addition, the complex causes accumulation of ubiquitinated proteins, induces apoptosis and inhibits cell proliferation, indicating its great potential as a novel therapy for triple‐negative breast cancer.     

A Bis-Chelating / Ligand for the Synthesis of Heterobimetallic Platinum(II)/Rhenium(I) Complexes: Tools for the Optimization of a New Class of Platinum(II) Anticancer Agents

The two independent and coordination sites of a newly synthesized bis[2-(hydroxyphenyl)-1,2,4-triazole] platform have been exploited to prepare four monometallic neutral ()Pt^II complexes carrying DMSO, pyridine, triphenylphosphine, or N-heterocyclic carbene as the fourth ligand. Then, the second coordination site was used to introduce an IR-active rhenium tricarbonyl entity, affording the four corresponding heterobimetallic neutral Pt^II/Re^I complexes, as well as a cationic Pt^II/Re^I derivative. X-ray crystallographic studies showed that distortion of the organic platform occurred to accommodate the coordination geometry of both metal centers. No ligand exchange or transchelation occurred upon incubation of the Pt^II complexes in aqueous environment or in the presence of Fe^III, respectively. The antiproliferative activity of the ligand and complexes was first screened on the triple-negative breast cancer cell line MDA-MB-231. Then, the IC₅₀ values of the most active candidates were determined on a wider panel of human cancer cells (MDA-MB-231, MCF-7, and A2780), as well as on a nontumorigenic cell line (MCF-10A). Low micromolar activities were reached for the complexes carrying a DMSO ligand, making them the first examples of highly active, but hydrolytically stable, Pt^II complexes. Finally, the characteristic mid-IR signature of the {Re(CO)₃} fragment in the Pt/Re heterobimetallic complexes was used to quantify their uptake in breast cancer cells.     

Low‐Magnetization Magnetic Microcapsules: A Synergistic Theranostic Platform for Remote Cancer Cells Therapy and Imaging

Multifunctional magnetic microcapsules (MMCs) for the combined cancer cells hyperthermia and chemotherapy in addition to MR imaging are successfully developed. A classical layer‐by‐layer technique of oppositely charged polyelectrolytes (poly(allylamine hydrochloride) (PAH) and poly(4‐styrene sulfonate sodium) (PSS)) is used as it affords great controllability over the preparation together with enhanced loading of the chemotherapeutic drug (doxorubicin, DOX) in the microcapsules. Superparamagnetic iron oxide (SPIOs) nanoparticles are layered in the system to afford MMC1 (one SPIOs layer) and MMC2 (two SPIOs layers). Most interestingly, MMC1 and MMC2 show efficient hyperthermia cell death and controlled DOX release although their magnetic saturation value falls below 2.5 emu g^?1, which is lower than the 7–22 emu g^?1 reported to be the minimum value needed for biomedical applications. Moreover, MMCs are pH responsive where a pH 5.5 (often reported for cancer cells) combined with hyperthermia increases DOX release predictably. Both systems prove viable when used as T2 contrast agents for MR imaging in HeLa cells with high biocompatibility. Thus, MMCs hold a great promise to be used commercially as a theranostic platform as they are controllably prepared, reproducibly enhanced, and serve as drug delivery, hyperthermia, and MRI contrast agents at the same time.     

Development of simultaneous analysis of tryptophan metabolites in serum and gastric juice – an investigation towards establishing a biomarker test for gastric cancer diagnosis

To evaluate changes in tryptophan metabolism and discover diagnostic biomarkers for gastric cancer, a quantitative method was developed for tryptophan and its seven metabolites (indole‐3‐lactic acid, anthranilic acid, serotonin, nicotinic acid, kynurenic acid, kynurenine and 3‐indoxyl sulfate) in both human serum and gastric juice using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Serum and gastric juice were prepared with a simple protein precipitation using aqueous 0.1% formic acid and acetonitrile. As a result, it was found that the kynurenine pathway of tryptophan metabolism was activated in gastric cancer and that the metabolic ratio of kynurenine/tryptophan, which reflects the enzyme activity of indoleamine‐2,3‐dioxygenase, was associated with the observed metabolic changes. Finally, the investigation of tryptophan metabolites, especially kynurenic acid, in serum and gastric juice might serve as biomarkers for gastric cancer. The findings in this study provide critical information of tryptophan metabolism which can be applied to a serum‐based diagnostic test for gastric cancer.     

FHIT-Substrate Complexes: a New Paradigm in Reversible Protein Phosphorylation

Fhit is a tumor suppressor protein encoded at the most fragile site in the human genome that is inactivated by genetic deletions early in the development of many cancers. A member of the Histidine Triad (HIT) superfamily of nucleotide-binding proteins, Fhit binds diadenosine triphosphate (ApppA) and cleaves it to produce AMP + ADP. The His96Asn mutation of Fhit, which reduces k_cat by more than a million-fold, does not reduce tumor suppressor activity in a nude mouse assay. Thus, genetic and biochemical evidence suggest that ApppA binding but not cleavage is required for tumor suppression. Crystal structures of Fhit bound to a nonhydrolyzable ApppA analog revealed that Fhit binds two substrates per dimer, presenting all of the phosphates and two of the adenosines on the surface of the protein in place of a deep, positively charged groove in the empty Fhit protein dimer. It is proposed that signaling by Fhit is mediated by presentation of nucleotide substrates to cytosolic effectors.