Mitochondria Of Tumor Cells Research Articles

Developing an Arene Binuclear Ruthenium(II) Complex to Induce Ferroptosis and Activate the cGAS-STING Pathway: Targeted Inhibiting Growth and Metastasis of Triple Negative Breast Cancer.

To effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC), we developed a high-efficiency and low-toxicity arene ruthenium (Ru) complex based on apoferritin (AFt). To achieve this, we optimized a series of Ru(II) 1,10-phenanthroline-2,9-diformaldehyde thiosemicarbazone complexes by studying their structure-activity relationships to obtain an arene binuclear Ru(II) complex (C5) with significant cytotoxicity and high accumulation in the mitochondria of tumor cells. Subsequently, a C5-AFt nanoparticle (NPs) delivery system was constructed. We found that the C5/C5-AFt NPs effectively inhibited TNBC growth and metastasis with few side effects. The C5-AFt NPs improved the anticancer and targeting abilities of C5 in vivo. Moreover, we confirmed the mechanism by which C5/C5-AFt NPs inhibit tumor growth and metastasis via mitochondrial damage-mediated ferroptosis and activation of the cGAS-STING pathway.

Tumor microenvironment-responsive manganese-based nano-modulator activate the cGAS-STING pathway to enhance innate immune system response

BackgroundManganese ions (Mn2+) combined with adjuvants capable of damaging and lysing tumor cells form an antitumor nano-modulator that enhances the immune efficacy of cancer therapy through the cascade activation of the cyclic GMP-AMP interferon gene synthase-stimulator (cGAS-STING) pathway, which underscores the importance of developing antitumor nano-modulators, which induce DNA damage and augment cGAS-STING activity, as a critical future research direction.Methods and ResultsWe have successfully synthesized an antitumor nano-modulator, which exhibits good dispersibility and biosafety. This nano-modulator is engineered by loading manganese dioxide nanosheets (M-NS) with zebularine (Zeb), known for its immunogenicity-enhancing effects, and conducting targeted surface modification using hyaluronic acid (HA). After systemic circulation to the tumor site, Mn2+, Zeb, and reactive oxygen species (ROS) are catalytically released in the tumor microenvironment by H+ and H2O2. These components can directly or indirectly damage the DNA or mitochondria of tumor cells, thereby inducing programmed cell death. Furthermore, they promote the accumulation of double-stranded DNA (dsDNA) in the cytoplasm, enhancing the activation of the cGAS-STING signalling pathway and boosting the production of type I interferon and the secretion of pro-inflammatory cytokines. Additionally, Zeb@MH-NS enhances the maturation of dendritic cells, the infiltration of cytotoxic T lymphocytes, and the recruitment of natural killer cells at the tumor site.ConclusionsThis HA-modified manganese-based hybrid nano-regulator can enhance antitumor therapy by boosting innate immune activity and may provide new directions for immunotherapy and clinical translation in cancer.Graphical

Mitochondria-targeting nanozyme for catalytical therapy and radiotherapy with activation of cGAS-STING

BackgroundOvercoming radio-resistance and enhance radio-sensitivity to obtain desired therapeutic outcome plays an important role in treating cancer. MethodsHere we constructed a versatile enzyme-like nano-radiosensitizer MDP. MDP is composed of MnCO decorated and Ru-based nanozyme with triphenylphosphine (TPP) group coordinated on the surface. ResultsDue to the mitochondria-targeting ability of TPP and enhanced permeability and retention effect (EPR) effect of MDP, MDP accumulated in the mitochondria of tumor cells. Therefore, quantities of reactive oxygen species were produced via multiple enzyme-like properties including peroxidase (POD) and catalase (CAT) in a tumor microenvironment mimicking status. In additional, more energy of radiation ionizing was deposed in tumor site via Compton effect and secondary electron scattering by Ru element. Impressively, it was disclosed that the nanozyme can act as a cGAS-STING agonist to provoke immune response of the system, which hereby further elevated this combined therapy. ConclusionsCollectively, we fabricated a novel nanozyme with POD and CAT mimicking properties for the combination therapy of catalytical therapy, radiotherapy as well as immune therapy to eliminate cancer.

Enhanced photodynamic therapy through multienzyme-like MOF for cancer treatment.

Overcoming resistance to apoptosis is a major challenge in cancer therapy. Recent research has shown that manipulating mitochondria, the organelles critical for energy metabolism in tumor cells, can increase the effectiveness of photodynamic therapy and trigger apoptosis in tumor cells. However, there is currently insufficient research and effective methods to exploit mitochondrial damage to induce apoptosis in tumor cells and improve the effectiveness of photodynamic therapy. In this study, we present a novel nanomedicine delivery and therapeutic system called PyroFPSH, which utilizes a nanozymes-modified metal-organic framework as a carrier. PyroFPSH exhibits remarkable multienzyme-like activities, including glutathione peroxidase (GPx) and catalase (CAT) mimicry, allowing it to overcome apoptosis resistance, reduce endogenous glutathione levels, and continuously generate reactive oxygen species (ROS). In addition, PyroFPSH can serve as a carrier for the targeted delivery of sulfasalazine, a drug that can induce mitochondrial depolarization in tumor cells, thereby reducing oxygen consumption and energy supply in the mitochondria of tumor cells and weakening resistance to other synergistic treatment approaches. Our experimental results highlight the potential of PyroFPSH as a versatile nanoplatform in cancer treatment. This study expands the biomedical applications of nanomaterials as platforms and enables the integration of various novel therapeutic strategies to synergistically improve tumor therapy. It deepens our understanding of multienzyme-mimicking active nanocarriers and mitochondrial damage through photodynamic therapy. Future research can further explore the potential of PyroFPSH in clinical cancer treatment and improve its drug loading capacity, biocompatibility and targeting specificity. In summary, PyroFPSH represents a promising therapeutic approach that can provide new insights and possibilities for cancer treatment.

F16 Hybrids Derived from Steviol or Isosteviol Are Accumulated in the Mitochondria of Tumor Cells and Overcome Drug Resistance.

Steviol and isosteviol were prepared from the commercially available sweetener stevioside and converted into lipophilic F16 hybrids. Their cytotoxicity was determined in SRB assays and showed to depend on both the substitution pattern of the aromatic substituent as well as on the spacer length. Therefore, compound 25 held an IC50 (A2780) of 180 nM, thus surpassing the activity of comparable rhodamine hybrids. Several of the compounds were also able to overcome drug resistance in the A2780/A2780cis model. Extra staining experiments showed a similar subcellular accumulation pattern of the F16 hybrids as a well-established mitocan, hence proving preferential mitochondrial accumulation but also some other accumulation in other cellular areas.

The mechanisms of action of mitochondrial targeting agents in cancer: inhibiting oxidative phosphorylation and inducing apoptosis.

The tumor microenvironment affects the structure and metabolic function of mitochondria in tumor cells. This process involves changes in metabolic activity, an increase in the amount of reactive oxygen species (ROS) in tumor cells compared to normal cells, the production of more intracellular free radicals, and the activation of oxidative pathways. From a practical perspective, it is advantageous to develop drugs that target mitochondria for the treatment of malignant tumors. Such drugs can enhance the selectivity of treatments for specific cell groups, minimize toxic effects on normal tissues, and improve combinational treatments. Mitochondrial targeting agents typically rely on small molecule medications (such as synthetic small molecules agents, active ingredients of plants, mitochondrial inhibitors or autophagy inhibitors, and others), modified mitochondrial delivery system agents (such as lipophilic cation modification or combining other molecules to form targeted mitochondrial agents), and a few mitochondrial complex inhibitors. This article will review these compounds in three main areas: oxidative phosphorylation (OXPHOS), changes in ROS levels, and endogenous oxidative and apoptotic processes.

Photoactivated DNA Nanodrugs Damage Mitochondria to Improve Gene Therapy for Reversing Chemoresistance.

Multidrug resistance (MDR) is a major cause of chemotherapy failure in oncology, and gene therapy is an excellent measure to reverse MDR. However, conventional gene therapy only modulates the expression of MDR-associated proteins but hardly affects their existing function, thus limiting the efficiency of tumor treatment. Herein, we designed a photoactivated DNA nanodrug (MCD@TMPyP4@DOX) to improve tumor chemosensitivity through the downregulation of MDR-related genes and mitochondria-targeted photodynamic therapy (PDT). The self-assembled DNA nanodrug encodes the mucin 1 (MUC1) aptamer and the cytochrome C (CytC) aptamer to facilitate its selective targeting to the mitochondria in tumor cells; the encoded P-gp DNAzyme can specifically cleave the substrate and silence MDR1 mRNA with the help of Mg2+ cofactors. Under near-infrared (NIR) light irradiation, PDT generates reactive oxygen species (ROS) that precisely damage the mitochondria of tumor cells and break single-stranded DNA (ssDNA) to activate MCD@TMPyP4@DOX self-disassembly for release of DOX and DNAzyme. We have demonstrated that this multifunctional DNA nanodrug has high drug delivery capacity and biosafety. It enables downregulation of P-gp expression while reducing the ATP on which P-gp pumps out drugs, improving the latency of gene therapy and synergistically reducing DOX efflux to sensitize tumor chemotherapy. We envision that this gene-modulating DNA nanodrug based on damaging mitochondria is expected to provide an important perspective for sensitizing tumor chemotherapy.

Platinum-Based Mcl-1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199.

Discovery of small molecule inhibitors targeting Mcl-1 (Myeloid cell leukemia 1) confronts many challenges. Based on the fact that Mcl-1 is mainly localized in mitochondria, we propose a new strategy of targeting mitochondria to improve the binding efficiency of Mcl-1 inhibitors. We report the discovery of complex 9, the first mitochondrial targeting platinum-based inhibitor of Mcl-1, which selectively binds to Mcl-1 with high binding affinity. Complex 9 was mainly concentrated in the mitochondria of tumor cells which led to an enhanced antitumor efficacy. Complex 9 induced Bax/Bak-dependent apoptosis in LP-1 cells and synergized with ABT-199 to kill ABT-199 resistant cells in multiple cancer models. Complex 9 was effective and tolerable as a single agent or in combination with ABT-199 in mouse models. This research work demonstrated that developing mitochondria-targeting Mcl-1 inhibitors is a new potentially efficient strategy for tumor therapy.

5‑aminiolevulinic acid induces a radiodynamic effect with enhanced delayed reactive oxygen species production under hypoxic conditions in lymphoma cells: An invitro study.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of intracranial tumor. However, PCNSL is radiosensitive; thus, whole-brain radiotherapy (WBRT) is often selected as an alternative consolidation therapy. WBRT-related delayed neurotoxicity can affect the quality of life of the elderly. 5-aminolevulinic acid (ALA) is a natural precursor of heme and has been widely used as a live molecular fluorescence marker in brain tumor surgery. Experimental studies have demonstrated that combination therapy with 5-ALA and ionizing irradiation (IR), denoted radiodynamic therapy (RDT), resulted in tumor suppression in cancer, including glioma, melanoma, colorectal cancer, prostate cancer, breast cancer and lung cancer; however, to the best of our knowledge, this method has not been investigated in lymphoma. The present study aimed to investigate the radiodynamic effect of 5-ALA on lymphoma cells in vitro. The synthesis of 5-ALA-induced protoporphyrin IX (PpIX) was assessed under normal and hypoxic conditions in lymphoma cells (Raji, HKBML and TK). Subsequently, the radiodynamic effect of 5-ALA was evaluated using a colony formation assay and reactive oxygen species (ROS) production after RDT was examined using flow cytometry. Finally, the mitochondrial density in the lymphoma cells was evaluated. Lymphoma cells exhibited a high accumulation of 5-ALA-induced PpIX in the flow cytometric analysis, and a decrease in the surviving fraction under IR in cells with 5-ALA treatment compared with cells not treated with 5-ALA in the colony formation assay under normal and hypoxic conditions. Although ROS production 12 h after IR was increased compared with that immediately after IR (0 h), pretreatment with 5-ALA enhanced the delayed ROS production in each lymphoma cell line under normoxic conditions. Raji and TK cells exhibited an increase in ROS production 12 h after IR compared with that at 0 h in the 5-ALA-untreated cells under hypoxic conditions. Raji, HKBML and TK cells exhibited an increase in ROS production 12 h after IR compared with that at 0 h in the 5-ALA-treated cells, while TK cells exhibited enhancement of ROS production 12 h after IR in 5-ALA-treated cells compared with 5-ALA-untreated cells under hypoxic conditions. Other studies have demonstrated that impaired mitochondria damaged by IR produce ROS via the metabolic process, then damage the rest of the surrounding normal mitochondria, consequently propagating oxidative stress within tumor cells and leading to cell death. Thus, we hypothesized that the propagating oxidative stress after IR was associated with mitochondrial density in tumor cells. Namely, high accumulation of 5-ALA-indcued PpIX may promote ROS production in mitochondria of tumor cells after IR, and suppress the cell surviving fraction via the propagation of oxidative stress. In the colony formation assay, Raji cell colony formation was suppressed by RDT with 5-ALA. Simultaneously, the mitochondrial density in the Raji cells was higher than that in other cell lines. Pretreatment with 5-ALA enhanced delayed ROS production after IR in lymphoma cells under normoxic conditions. Under hypoxic conditions, only TK cells exhibited enhancement of ROS production 12 h after IR in the 5-ALA-treated group compared with the 5-ALA-untreated group. Although further studies evaluating the effect of hypoxic conditions in lymphoma cells are needed, the results suggested that RDT with 5-ALA could suppress colony formation under normal and hypoxic conditions in lymphoma cells. Therefore, RDT with 5-ALA is a potential treatment option for PCNSL.

Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5h to ∼1.5h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy.

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.

Gold nanoparticles inhibit tumor growth via targeting the Warburg effect in a c-Myc-dependent way.

Gold nanoparticles (AuNPs) are prospective tools for nano-based medicine that can directly target cellular biological processes to influence cell fate and function. Studies have revealed the essential role of AuNPs in metabolic remodeling for macrophage polarization. Nevertheless, as a hallmark of cancer cells, metabolic changes in tumor cells in response to AuNPs have not yet been reported. In the present study, polymer- and folate-conjugated AuNPs with satisfactory biocompatibility and tumor-targeting activity were synthesized to investigate their underlying roles in tumor metabolism. Tumor cells were significantly suppressed by AuNPs in vitro and in vivo, with little cytotoxicity in non-tumor cells. Subcellular localization showed that AuNPs localized in the mitochondria of tumor cells and impaired their structure and function, leading to excessive oxidative stress and mitochondrial apoptosis. Metabolic stress, with decreased glycolysis and insufficient nutrients, was also caused by AuNPs exposure in tumor cells. Mechanistically, the key enzymes (GLUT1 and HK2) for glycolysis modulation were remarkably reduced by AuNPs in a c-Myc-dependent manner. The present study demonstrated a new mechanism for AuNPs in the inhibition of tumor growth, that is, via directly targeting glycolysis and depriving energy. These findings provide new strategies for the design of nano-based medicines and anti-glycolytic therapeutics to inhibit the development of malignant tumors. STATEMENT OF SIGNIFICANCE: Gold nanoparticles (AuNPs) have acquired ever-increasing interest for applications in cancer treatment and diagnosis due to their high biosafety and facile surface modification. Recent studies have shown that AuNPs can work as active agents to directly target the cellular processes and harbor antitumor properties, while the underlying mechanisms remain largely unknown. From the present findings, the stabilized AuNPs showed direct inhibition effects on tumor growth by glycolysis inhibition and energy deprivation. These results provide new insights of AuNPs for tumor treatments, which will further contribute to the development of promising nano-based medicines and anti-glycolytic therapies.

The development and evaluation of hyaluronic acid coated mitochondrial targeting liposomes for celastrol delivery

In order to precisely deliver celastrol into mitochondria of tumor cells, improve antitumor efficacy of celastrol and overcome its troublesome problems in clinical application, a novel multistage-targeted celastrol delivery system (C-TL/HA) was developed via electrostatic binding of hyaluronic acid (HA) to celastrol-loaded cationic liposomes composed of natural soybean phosphatidylcholine and cholesterol modified with mitochondrial targeting molecular TPP. Study results in this article showed that C-TL/HA successfully transported celastrol into mitochondria, effectively activated apoptosis of mitochondrial pathway, exerted higher tumor inhibition efficiency and lower toxic side effects compared with free celastrol. More importantly, HA coating not only enabled this delivery system to have good stability and safety in vivo, but also increased drug uptake and facilitated tumor targeting through recognizing CD44 receptors rich on the surface of tumor cells. Conclusively, this HA-coated mitochondrial targeting liposomes may provide a prospect for the clinical application of celastrol in tumor therapy.

Inhibition of Non-small Cell Lung Cancer by Ferroptosis and Apoptosis Induction through P53 and GSK-3β/Nrf2 Signal Pathways using Qingrehuoxue Formula.

This study aimed to elucidate the effects of Qingrehuoxue Formula (QRHXF) on NSCLC and its underlying mechanisms. Nude mouse model of subcutaneous tumors was established. QRHXF and erastin were administered orally and intraperitoneally, respectively. Mice's body weight and subcutaneous tumor volumes were measured. The effects of QRHXF on epithelial-mesenchymal transition (EMT), tumor-associated angiogenesis and matrix metalloproteinases (MMPs) were assessed. Importantly, we also analysed the anti-NSCLC of QRHXF form the aspect of ferroptosis and apoptosis and investigate its underlying mechanisms. The safety of QRHXF in mice was also evaluated. QRHXF slowed down the speed of tumor growth and visibly inhibited tumor growth. The expression levels of CD31, VEGFA, MMP2 and MMP9 were prominently suppressed by QRHXF. Furthermore, QRHXF appeared to remarkably inhibite cell proliferation and EMT by decreasing Ki67, N-cadherin and vimentin expression but elevating E-cadherin expression. There were more apoptotic cells in QRHXF group's tumor tissues, and QRHXF treatment increased BAX and cleaved-caspased 3 levels but decreased Bcl-2 levels. QRHXF significantly increased the accumulation of ROS, Fe2+, H2O2, and MDA while reduced GSH levels. SLC7A11 and GPX4 protein levels were considerably suppressed by QRHXF treatment. Moreover, QRHXF triggered ultrastructural changes in the mitochondria of tumor cells. The levels of p53 and p-GSK-3β were upregulated, whereas that of Nrf2 was downregulated in the groups treated with QRHXF. QRHXF displayed no toxicity in mice. QRHXF activated ferroptosis and apoptosis to suppress NSCLC cell progression via p53 and GSK-3β/Nrf2 signaling pathways.

Self-reported and self-facilitated theranostic oxygen nano-economizer for precise and hypoxia alleviation-potentiated photodynamic therapy.

Photodynamic therapy (PDT) has been extensively investigated for cancer treatment by virtue of singlet oxygen-induced oxidative damage to tumors. Nevertheless, the therapeutic efficiency of PDT is still limited by the low singlet oxygen yield attributed to the improper irradiation duration and the tumor hypoxic microenvironment. To tackle these challenges, we elaborately design a theranostic oxygen nano-economizer to self-report the optimal irradiation duration and alleviate tumor hypoxia simultaneously, which is engineered by fluorescent 9,10-anthracenyl bis (benzoic acid) (DPA)-MOF, tetrakis (4-carboxyphenyl) porphyrin (TCPP), triphenyl phosphine (TPP) and redox-responsive lipid-PEG (DSPE-SS-PEG2k). Upon laser irradiation, the fluorescence of DPA-MOF could be quenched, thereby self-reporting the optimal irradiation duration for sufficient PDT. The decoration of DSPE-SS-PEG2k and TPP endows the theranostic oxygen nano-economizer with a tumor-specific response and mitochondrial targeting capability, respectively. Notably, singlet oxygen generated from TCPP reduces oxygen consumption by disrupting the entire oxidative phosphorylation (OXPHOS) pathway in the mitochondria of tumor cells, further improving the level of singlet oxygen in a self-facilitated manner for hypoxia alleviation-potentiated PDT. As expected, such a self-reported and self-facilitated theranostic oxygen nano-economizer exhibits potent antitumor activity in the 4T1 tumor-bearing mouse model. This study offers a theranostic paradigm for precise and hypoxia alleviation-potentiated cancer therapy.

Mitochondria-Targeted Ergosterol Peroxide Derivatives: Synthesis, Anticancer Properties and Their Preliminary Mechanism of Inhibiting MCF-7 Cell Proliferation

Ergosterol peroxide (EP) has been extensively studied for its antitumor activities. However, its further development has been restricted due to its limited intracellular accumulation and poor aqueous solubility. In this study, a novel triphenylphosphonium cation (TPP+) moiety was coupled to ergosterol peroxide to precisely target it at tumor cell mitochondria. The synthesized Mito-EP derivatives Mito-EP-3a-3d displayed stronger cytotoxicity than the EP parent and exhibited selectively cytotoxic effects between cancer cells and normal gastric epithelial (GES-1) cells. The most potent compound, Mito-EP-3b, was 9.7-fold more efficacious than ergosterol peroxide in the MCF-7 (breast cancer) cell line and showed good selectivity (SI = IC50GES-1/IC50MCF-7 = 4.04, IC50: concentrations to inhibit 50% of cell growth). Furthermore, Mito-EP-3b was able to decrease the mitochondrial membrane potential and induced reactive oxygen species production, accompanied by activating the expression of cytochrome c and Bax, while Bcl-2 expression was suppressed. The molecular mechanism may refer to the mitochondrial apoptotic pathway. Overall, the above results incentivize the further study of Mito-EP-3b derivatives as potent anticancer agents.

Inclusion of the in-chain sulfur in 3-thiaCTU increases the efficiency of mitochondrial targeting and cell killing by anticancer aryl-urea fatty acids

Mitochondria in tumor cells are functionally different from those in normal cells and could be targeted to develop new anticancer agents. We showed recently that the aryl-ureido fatty acid CTU is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells by increasing the production of reactive oxygen species (ROS), activating endoplasmic reticulum (ER)-stress and promoting apoptosis. However, prolonged treatment with high doses of CTU were required for in vivo anti-tumor activity. Thus, new strategies are now required to produce agents that have enhanced anticancer activity over CTU. In the present study we prepared a novel aryl-urea termed 3-thiaCTU, that contained an in-chain sulfur heteroatom, for evaluation in tumor cell lines and in mice carrying tumor xenografts. The principal finding to emerge was that 3-thiaCTU was several-fold more active than CTU in the activation of aryl-urea mechanisms that promoted cancer cell killing. Thus, in in vitro studies 3-thiaCTU disrupted the mitochondrial membrane potential, increased ROS production, activated ER-stress and promoted tumor cell apoptosis more effectively than CTU. 3-ThiaCTU was also significantly more active than CTUin vivo in mice that carried MDA-MB-231 cell xenografts. Compared to CTU, 3-thiaCTU prevented tumor growth more effectively and at much lower doses. These findings indicate that, in comparison to CTU, 3-thiaCTU is an aryl-urea with markedly enhanced activity that could now be suitable for development as a novel anticancer agent.

Synthesis, characterization and biological evaluation of two cyclometalated iridium(III) complexes containing a glutathione S-transferase inhibitor

The cyclometalated iridium(III) compounds have been intensively studied for health-related applications due to their outstanding luminescent properties and multiple anticancer modes of action. Herein, two iridium(III) compounds Ir-1 and Ir-3 containing glutathione S-transferase inhibitor (GSTi) were developed and studied together with two unfunctionalized compounds Ir-2 and Ir-4 as a comparison. Biological study indicated that GSTi-bearing complexes Ir-1 and Ir-3 exert a synergistic effect on the inhibition of cancer cells. The photophysical properties of Ir-1 ∼ Ir-4 were investigated by UV/vis absorption and fluorescence spectroscopy and rationalized with TD-DFT calculations. As expected, GSTi-bearing complexes Ir-1 and Ir-3 exhibited considerable cytotoxicity against both A549 and cisplatin-resistant A549/cis cancer cells, much higher than the unfunctionalized iridium compounds Ir-2 and Ir-4. Further study indicated that Ir-1 and Ir-3 mainly localize in the mitochondria of tumor cells, and exert their cytotoxicity via generating ROS and inhibiting GST activity. The flow cytometry investigations demonstrated that Ir-1 and Ir-3 can arrest the cell cycle in S phase and induce the cell death through apoptosis process. Overall, the complexation of GST inhibitors with cyclometalated iridium(III) agents provides an effective way for potentiating the cytotoxicity of iridium(III) anticancer agents and resensitizing the efficacy against cisplatin resistant cancer cells.

Biosynthetic Dendritic Cell-Exocytosed Aggregation-Induced Emission Nanoparticles for Synergistic Photodynamic Immunotherapy.

Dendritic cell (DC)-derived small extracellular vesicles (DEVs) are recognized as a highly promising alternative to DC vaccines; however, the clinical testing of DEV-based immunotherapy has shown limited therapeutic efficacy. Herein, we develop a straightforward strategy in which DCs serve as a cell reactor to exocytose high-efficient DEV-mimicking aggregation-induced emission (AIE) nanoparticles (DEV-AIE NPs) at a scaled-up yield for synergistic photodynamic immunotherapy. Exocytosed DEV-AIE NPs inherit not only the immune-modulation proteins from parental DCs, enabling T cell activation, but also the loaded AIE-photosensitizer MBPN-TCyP, inducing superior immunogenic cell death (ICD) by selectively accumulating in the mitochondria of tumor cells. Eventually, DEV-AIE synergistic photodynamic immunotherapy elicits dramatic immune responses and efficient eradication of primary tumors, distant tumors, and tumor metastases. In addition, cancer stem cells (CSCs) in 4T1 and CT26 solid tumors were significantly inhibited by the immune functional DEV-AIE NPs. Our work presents a facile method for the cellular generation of EV-biomimetic NPs and demonstrates that the integration of DEVs and AIE photosensitizers is a powerful direction for the production of clinical anticancer nanovaccines.

Mitochondrial therapy can inhibit melanoma development.

e21571 Background: Mitochondria of tumor cells undergo adaptive changes for even more active reproduction of tumor cells in the acidic and hypoxic microenvironment of tumor tissue. The purpose of this study was to evaluate antitumor effect of mitochondrial therapy in BALB/c Nude mice of both genders with B16/F10 melanoma growth. Methods: Male (n = 10) and female (n = 10) BALB/c Nude mice were injected subcutaneously with 0.5 ml of a suspension of B16/F10 mouse melanoma tumor cells in saline at a dilution of 1:20. Mitochondria (MC) were isolated from rat liver. 24 hours after subcutaneous transplantation of B16/F10 melanoma, mice were intraperitoneally injected with freshly isolated mitochondria (3.3 mg of protein per animal in 0.3 ml of saline). Further, mitochondrial therapy (MC therapy) was carried out according to the scheme on days 3, 5, 9, 13, 16, 19, 21. Male BALB/c Nude mice with subcutaneous inoculation of B16/F10 melanoma receiving intraperitoneal injections with 0.3 ml of saline served as controls. Results: Subcutaneous tumors in mice of both genders could be determined on the 5th day from the moment of tumor transplantation. In males, the regressive effect of MC therapy was recorded from the 8th day of tumor growth. The average tumor volume in males with MC therapy on day 8 was 3.0 times less than in the control group. On days 12 and 15, the regressive difference in tumor volumes between the groups was 1.8 times (p < 0.05) (MC therapy). On day 19, a slower tumor growth was recorded in the group with MC therapy, where the tumor volume was 2 times lower compared to the control volumes. At the end of the experiment on day 22, the difference in the average tumor volumes was 3.2 times, i.e. a significant inhibition of tumor growth was determined in males treated with MC therapy. A sizeable tumor node in females treated with MC therapy formed longer than in males, remaining as a flat tumor spot for up to 8 days. The inhibition of the growth of a large tumor node was determined on day 12 of melanoma growth, and the difference with the control values was 1.8 times (p < 0.05). On day 15, the tumor volumes in females with MC therapy decreased by 2.2 times compared with the control values, on day 19 - by 2.1 times. As a result, by the end of the experiment (day 22), the difference with the control group was 2.7 times. Conclusions: MC therapy inhibits the growth of B16/F10 melanoma in male and female BALB/c Nude mice. Formation of a sizeable tumor node and the start the tumor growth inhibition differs in time depending on the gender of experimental animals.