Host-guest interactions based supramolecular complexes self-assemblies for amplified chemodynamic therapy with H2O2 elevation and GSH consumption properties

Although endogenous H₂O₂ is overexpressed in tumor tissue, the amount of endogenous H₂O₂ is still insufficient for chemodynamic therapy (CDT). In addition, the abundant cellular glutathione (GSH) could also consume ^?OH for reduced CDT. Thus, the elevation of H₂O₂ and the consumption of GSH in tumor tissue are essential for the increased ^?OH yield and amplified CDT efficacy. In this paper, host-guest interactions based supramolecular complexes self-assemblies (SCSAs) were fabricated by incorporating cinnamaldehyde (CA) and PEG-modified cyclodextrin host units (mPEG-CD-CA) with ferrocene-(phenylboronic acid pinacol ester) conjugates (Fc-BE) on the basis of CD-induced host-guest interactions. After being internalized by cancer cells, CA can be released from SCSAs through the pH-responsive acetal linkage, elevating the H₂O₂ level by activating NADPH oxidase. Then, Fc can catalyze the H₂O₂ to higher cytotoxic hydroxyl radicals (^?OH). Moreover, quinone methide (QM) can be produced through H₂O₂-induced aryl boronic ester rearrangement and further consume the antioxidant GSH. In vitro and in vivo experiments demonstrate that SCSAs can be provided as potential amplified CDT nanoagents.     

Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.     

In vitro antitumor activity of water-soluble copper(I) complexes with diimine and monodentate phosphine ligands

Copper(I) complexes including diimine ligands of the bicinchoninic acid (BCA) and bathocuproinedisulfonic acid (BCS) families and water-soluble phosphines have been synthetized, characterized and investigated for their in vitro anticancer potential against human tumor cell lines representing examples of lung, breast, pancreatic and colon cancers and melanoma. All copper complexes exhibited moderate to high cytotoxic activity and the ability to overcome cisplatin resistance. Remarkably, growth-inhibitory effects evaluated in human non-transformed cells revealed a preferential cytotoxicity versus neoplastic cells. The remarkable cytotoxic effect towards BxPC3 pancreatic cancer cells, notoriously poor sensitive to cisplatin, was not related to a DNA or proteasome damage.     

A melatonin-based targetable fluorescent probe for screening of tumor cells and real-time imaging of glutathione fluctuations in tumor cells

Glutathione(GSH) is a key maintainer of cellular redox balance and plays an important role in many physiological effects. For example, GSH has been widely implicated in cancer initiation, progression and metastasis. Moreover, the concentrations of GSH in tumor cells can influence drug resistance. Given the serious harmfulness of cancer and the important roles of GSH in cancer, it has great significance to development probes for screening of tumor cells and real-time monitoring of GSH fluctuation...     

Diastereoselective amidoallylation of glyoxylic acid with chiral tert-butanesulfinamide and allylboronic acid pinacol esters: efficient synthesis of optically active γ,δ-unsaturated α-amino acids

A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of (R)-tert-butanesulfinamide and glyoxylic acid with molecular sieves in CH₂Cl₂ was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give (R)-2-((R)-tert-butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of (Z)-crotylboronic acid pinacol ester produced no product; however, that of (E)-crotylboronic acid pinacol ester produced (2R,3S)-2-((R)-tert-butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.     

Dual-Responsive Alginate Hydrogel Constructed by Sulfhdryl Dendrimer as an Intelligent System for Drug Delivery

Intelligent stimulus-triggered release and high drug-loading capacity are crucial requirements for drug delivery systems in cancer treatment. Based on the excessive intracellular GSH expression and pH conditions in tumor cells, a novel glutathione (GSH) and pH dual-responsive hydrogel was designed and synthesized by conjugates of glutamic acid-cysteine dendrimer with alginate (Glu-Cys-SA) through click reaction, and then cross-linked with polyethylene glycol (PEG) through hydrogen bonds to form a 3D-net structure. The hydrogel, self-assembled by the inner disulfide bonds of the dendrimer, is designed to respond to the GSH heterogeneity in tumors, with a remarkably high drug loading capacity. The Dox-loaded Glu-Cys-SA hydrogel showed controlled drug release behavior, significantly with a release rate of over 76% in response to GSH. The cytotoxicity investigation indicated that the prepared DOX-loaded hydrogel exhibited comparable anti-tumor activity against HepG-2 cells with positive control. These biocompatible hydrogels are expected to be well-designed GSH and pH dual-sensitive conjugates or polymers for efficient anticancer drug delivery.     

Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium-Betulin Immune Agonist

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl ( Ir-Bet ) was developed by a metal-ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]₂Cl₂ with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir-Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).     

Glutathione-Induced In Situ Michael Addition between Nanoparticles for Pyroptosis and Immunotherapy

Most tumor treatments will fail when ignoring competition and cooperation between each cancer cell and its microenvironment. Inspired by game theory, therapeutic agents can be introduced to compete for intracellular molecules to disrupt the cooperation between molecules and cells. Biomineralized oxidized (−)-epigallocatechin-3-o-gallate (EGCG)–molybdenum ion coordination nanoparticles were prepared for disrupting redox equilibria and simultaneously reacting with intracellular GSH in a Michael addition to form large aggregates that can mechanically disrupt endosomal and plasma membranes, stimulating pyroptosis and anti-tumor immunological responses for versatile inhibition of different types of tumors. This design disrupts the cooperation between molecules and between cancer and immune cells, achieving an optimal payoff in competition and cooperation in cancer therapy.     

Polymeric STING Pro-agonists for Tumor-Specific Sonodynamic Immunotherapy

The efficacy of combination immunotherapy has been limited by tumor specificity and immune-related adverse events (irAEs). Herein, we report the development of polymeric STING pro-agonists (PSPA), whose sono-immunotherapeutic efficacy is activated by sono-irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA-2) via the GSH-activatable linkers. Under sono-irradiation, PSPA serves as a sonosensitizer to generate ¹O₂ and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA-2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off-target side effects. The activation of the STING pathway elevates the interferon-β level and synergizes with SDT to enhance the anti-tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono-immunotherapy.     

Antiproliferative Activity of Functionalized Histidine‐derived Au(I) bis‐NHC Complexes for Bioconjugation

A series of histidine derived Au(I) bis‐NHC complexes bearing different ester, amide and carboxylic acid functionalities as well as wingtip substituents is synthesized and characterized. The stability in aqueous media, in vitro cytotoxicity in a set of cancer cell lines (MCF7, PC3 and A2780/A2780cisR) along with the cellular uptake are evaluated. Stability tests suggest hydrolysis of the ester within 8 h, which might lead to deactivation. Furthermore, the bis‐NHC system shows a sufficient stability against cysteine and the thiol containing peptide GSH. The benzyl ester and amide show the highest activity comparable to the benchmark compound cisplatin, with the ester only displaying a slightly lower cytotoxicity than the amide. A cellular uptake study revealed that the benzyl ester and the amide could have different intracellular distribution profiles but both complexes induce perturbations of the cellular physiological processes. The simple modifiability and high stability of the complexes provides a promising system for upcoming post modifications to enable targeted cancer therapy.     

Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes

Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and (1)H NMR spectroscopy. Their design was inspired by the observation that estrogen receptor-positive cells exposed to the hormone are sensitized to cisplatin. Intracellular reduction of bis-estrogen-cis-diamminedichloroplatinum(IV), BEP(n) (where n = 1-5 methylene groups between Pt and estrogen), occurs to afford cisplatin and two equivalents of the linker-modified estrogen. The ability of BEP(n) to induce overexpression of HMGB1 was established by immunofluorescence microscopy. The cytotoxicity of the compounds was evaluated in ER(+) MCF-7 and ER(-) HCC-1937 human breast cancer cell lines. BEP3 selectively induces overexpression of HMGB1 in MCF-7 cells, compared to HCC-1937 cells, and enhances their sensitivity (IC(50) = 2.1 +/- 0.4 microM versus 3.7 +/- 0.9 microM, respectively) to the compound. The difference in compound activities and the potential of compounds of this class for treating breast and ovarian cancer are discussed.     

Gallium Triggers Ferroptosis through a Synergistic Mechanism

The gallium ion (Ga³⁺) has long been believed to disrupt ferric homeostasis in the body by competing with iron cofactors in metalloproteins, ultimately leading to cell death. This study revealed that through an indirect pathway, gallium can trigger ferroptosis, a type of non-apoptotic cell death regulated by iron. This is exemplified by the gallium complex of the salen ligand ( Ga-1 ); we found that Ga-1 acts as an effective anion transporter that can affect the pH gradient and change membrane permeability, leading to mitochondrial dysfunction and the release of ferrous iron from the electron transfer chain (ETC). In addition, Ga-1 also targeted protein disulfide isomerases (PDIs) located in the endoplasmic reticulum (ER) membrane, preventing the repair of the antioxidant glutathione (GSH) system and thus enforcing ferroptosis. Finally, a combination treatment of Ga-1 and dietary polyunsaturated fatty acids (PUFAs), which enhances lipid peroxidation during ferroptosis, showed a synergistic therapeutic effect both in vitro and in vivo. This study provided us with a strategy to synergistically induce Ferroptosis in tumor cells, thereby enhancing the anti-neoplastic effect.     

alpha-Mangostin enhances betulinic acid cytotoxicity and inhibits cisplatin cytotoxicity on HCT 116 colorectal carcinoma cells

Despite the progress in colon cancer treatment, relapse is still a major obstacle. Hence, new drugs or drug combinations are required in the battle against colon cancer. α-Mangostin and betulinic acid (BA) are cytotoxic compounds that work by inducing the mitochondrial apoptosis pathway, and cisplatin is one of the most potent broad spectrum anti-tumor agents. This study aims to investigate the enhancement of BA cytotoxicity by α-mangostin, and the cytoprotection effect of α-mangostin and BA on cisplatin-induced cytotoxicity on HCT 116 human colorectal carcinoma cells. Cytotoxicity was investigated by the XTT cell proliferation test, and the apoptotic effects were investigated on early and late markers including caspases-3/7, mitochondrial membrane potential, cytoplasmic shrinkage, and chromatin condensation. The effect of α-mangostin on four signalling pathways was also investigated by the luciferase assay. α-Mangostin and BA were more cytotoxic to the colon cancer cells than to the normal colonic cells, and both compounds showed a cytoprotective effect against cisplatin-induced cytotoxicity. On the other hand, α-mangostin enhanced the cytotoxic and apoptotic effects of BA. Combination therapy hits multiple targets, which may improve the overall response to the treatment, and may reduce the likelihood of developing drug resistance by the tumor cells. Therefore, α-mangostin and BA may provide a novel combination for the treatment of colorectal carcinoma. The cytoprotective effect of the compounds against cisplatin-induced cytotoxicity may find applications as chemopreventive agents against carcinogens, irradiation and oxidative stress, or to neutralize cisplatin side effects.     

Synthesis of diarylazepan-4-ones

Synthesis of several 3,3-diarylazepan-4-ones and 5,5-diarylazepan-4-ones has been established starting from two tetrasubstituted olefins, which is derived from commercially available piperidine-3-carboxylic acid ethyl ester and piperidine-4-carboxylic acid ethyl ester. The single isomer with the structural skeleton of 3,3-diarylazepan-4-one and 5,5-diarylazepan-4-one is constructed in two functional group transformations of Grignard addition/dehydration and epoxidation/pinacol rearrangement.     

Catalytic immunotherapy-photothermal therapy combination for melanoma by ferroptosis-activating vaccine based on artificial nanoenzyme

Tumor cell vaccine is a promising approach for cancer therapy to activate tumor immune, which can be achieved by tumor cells immunogenic cell death (ICD), converting in situ tumors into endogenous vaccination strategy, and ferroptosis has been proved to induce ICD occurrence. Ferroptosis is triggered by artificial nanoenzyme copper telluride mimicking peroxidase and glutathione oxidase, based on which the ferroptosis-activating vaccine (termed as CM CTNPs@OVA) was designed and established for catalytic immunotherapy. Owing to photothermal effect of copper telluride, photothermal therapy (PTT) was combined for an intensive cancer therapeutic effect. CM CTNPs@OVA was composed of solid mesoporous copper telluride nanoparticles, ovalbumin (OVA) loaded in mesoporous, and melanoma cell membrane coating surface. In in vitro and in vivo investigations, CM CTNPs@OVA, with particle size of 113.7 ± 1.7 nm, was certified to release copper ions for ferroptosis initiation, and OVA directly maturated dendritic cell (DC) as exogenous antigens extracellularly. ICD was then induced by ferroptosis pathway and PTT to release damage-associated molecular patterns for DC maturation and subsequent T cells recruitment. CM CTNPs@OVA-treated melanoma with exited inhibition rate, proving that the strategy of catalytic immunotherapy-PTT combination by ferroptosis-activating vaccine possessed massive potential for melanoma therapy based on nanoenzyme copper telluride.     

Hydrogen Peroxide and Glutathione Dual Redox‐Responsive Nanoparticles for Controlled DOX Release

Polymer nanoparticulate drug delivery systems that respond to reactive oxygen species (ROS) and glutathione (GSH) simultaneously at biologically relevant levels hold great promise to improve the therapeutic efficacy to cancer cells with reduced side effects of chemo drugs. Herein, a novel redox dual‐responsive amphiphilic block copolymer (ABP) that consists of a hydrophilic poly (ethylene oxide) block and a hydrophobic block bearing disulfide linked phenylboronic ester group as pendant is synthesized, and the DOX loaded nanoparticles (BSN‐DOX) based on ABPs with varied hydrophobic block length are fabricated for DOX delivery. The self‐immolative leaving reaction of phenylboronic ester triggered by extracellular ROS and the cleavage of disulfide linkages induced by intracellular GSH both lead to rapid DOX release from BSN‐DOX, resulting in an on‐demand DOX release. Moreover, BSN‐DOX show better tumor inhibition and lower side effects in vivo compared with free drug.     

A convergent approach to gamma-carbonyl vinyl boronates

Gamma-carbonyl vinyl boronates can be prepared by a visible light induced radical chain addition of an S-acyl dithiocarbonate (xanthate) to the pinacol ester of vinyl boronic acid, followed by treatment with base.     

Valproic Acid Promotes Apoptosis and Cisplatin Sensitivity Through Downregulation of H19 Noncoding RNA in Ovarian A2780 Cells

Cisplatin resistance is one of the main limitations in the treatment of ovarian cancer, which is partly mediated by long noncoding RNAs (lncRNAs). H19 is a lncRNA involving in cisplatin resistance in cancers. Valproic acid (VPA) is a commonly used drug for clinical treatment of seizure disorders. In addition, this drug may display its effects through regulation of noncoding RNAs controlling gene expression. The aim of the present study was the investigation of VPA treatment effect on H19 expression in ovarian cancer cells and also the relation of the H19 levels with apoptosis and cisplatin resistance. Briefly, treatment with VPA not only led to significant increase in apoptosis rate, but also increased the cisplatin sensitivity of A2780/CP cells. We found that following VPA treatment, the expression of H19 and EZH2 decreased, but the expression of p21 and PTEN increased significantly. To investigate the involvement of H19 in VPA-induced apoptosis and cisplatin sensitivity, H19 was inhibited by a specific siRNA. Our results demonstrate that H19 knockdown by siRNA induced apoptosis and sensitized the A2780/CP cells to cisplatin-induced cytotoxicity. These data indicated that VPA negatively regulates the expression of H19 in ovarian cancer cells, which subsequently leads to apoptosis induction, cell proliferation inhibition, and overwhelming to cisplatin resistance. The implication of H19→EZH2→p21/PTEN pathway by VPA treatment suggests that we could repurpose an old drug, valproic acid, as an effective drug for treatment of ovarian cancer in the future.     

Lysosome‐Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS‐dependent prodrugs. In particular, known prodrug 4‐(N ‐ferrocenyl‐N ‐benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome‐specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC₅₀=3.5–7.2 μm ) and in vivo (40 mg kg⁻¹, NK/Ly murine model) but remained weakly toxic towards non‐malignant cells (IC₅₀=15–30 μm ).     

In vitro evaluation of apoptosis detection by 99mTc-tetrofosmin in MCF-7 breast cancer cell line

Radiolabeled molecules have an important role to evaluate tumor characteristics such as aggressiveness, and to identify the effectiveness of cancer treatments such as chemotherapy and radiotherapy. Various radionuclide (¹⁸F, ^99mTc, ¹²⁴I) labeled molecules can be used apoptosis detection by estimating decrescendos cell viability after therapy. ^99mTc-tetrofosmin which is used as a myocardial perfusion imaging agent in routine and at the same time is known to accumulate in various tumors including breast tumor. The aim of this study was to assess the utility of ^99mTc-tetrofosmin for monitoring the early response of MCF-7 breast cancer to chemotherapy. To evaluate the role of ^99mTc-tetrofosmin in vitro chemotherapy, the uptake ratio was determined using MCF-7 breast cancer line after the cells had been treated with cisplatin. When we examined the apoptotic ratios which induced with different dose of cisplatin in MCF-7 breast cancer cells by using Annexin V and TUNEL methods, it was observed that the rate of apoptosis increased with soaring dose. The uptake rates of ^99mTc-tetrofosmin in MCF-7 cell line in the chemotherapeutic groups were lower than it is in the control group (p < 0.01). The negative correlation between uptake ratios and apoptotic rates shows that ^99mTc-tetrofosmin may be used a radiopharmaceutical for evaluating chemotherapy response. ^99mTc-tetrofosmin might be probably useful as an imaging agent for estimation of early chemotherapy response in breast cancer.