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Metastatic triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and the accumulation of immunosuppressive cells. Herein, we designed a lenvatinib- and vadimezan-loaded synthetic high-density lipoprotein (LV-sHDL) for combinational immunochemotherapy of metastatic TNBC. The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection. The multitargeted tyrosine kinase inhibitor (TKI) lenvatinib induced immunogenic cell death of the cancer cells, and the stimulator of interferon genes (STING) agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation, which synergistically improved the intratumoral infiltration of total and active CTLs by 33- and 13-fold, respectively. LV-sHDL inhibited the growth of orthotopic 4T1 tumors, reduced pulmonary metastasis, and prolonged the survival of animals. The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1. This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.
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α-Mangostin and vadimezan are widely studied potential anticancer agents. Their biological activities may be improved by covalent bonding by amide or ester bonds with the third generation poly(amidoamine) (PAMAM) dendrimer, substituted with α-D-glucoheptono-1,4-lactone and biotin. Thus, conjugates of either ester- (G3gh4B5V) or amide-linked (G32B12gh5V) vadimezan, and equivalents of α-mangostin (G3gh2B5M and G32B12gh5M, respectively), were synthesized, characterized and tested in vitro against cancer cells: U-118 MG glioma, SCC-15 squamous carcinoma, and BJ normal human fibroblasts growth, as well as against C. elegans development. α-Mangostin cytotoxicity, stronger than that of Vadimezan, was increased (by 2.5-9-fold) by conjugation with the PAMAM dendrimer (with the amide-linking being slightly more effective), and the strongest effect was observed with SCC-15 cells. Similar enhancement of toxicity resulting from the drug conjugation was observed with C. elegans. Vadimezan (up to 200 µM), as well as both its dendrimer conjugates, was not toxic against both the studied cells and nematodes. It showed an antiproliferative effect against cancer cells at concentrations ≥100 µM. This effect was significantly enhanced after conjugation of the drug with the dendrimer via the amide, but not the ester bond, with G32B12gh5V inhibiting the proliferation of SCC-15 and U-118 MG cells at concentrations ≥4 and ≥12 µM, respectively, without a visible effect in normal BJ cells. Thus, the drug delivery system based on the PAMAM G3 dendrimer containing amide bonds, partially-blocked amino groups on the surface, larger particle diameter and higher zeta potential can be a useful tool to improve the biological properties of transported drug molecules.
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Naturally occurring flavonoids are found as secondary metabolites in a wide number of plants exploited for both medicine and food and have long been known to be endowed with multiple biological activities, making them useful tools for the treatment of different pathologies. Due to the versatility of the scaffolds and the vast possibilities of appropriate decoration, they have also been regarded as fruitful sources of lead compounds and excellent chemical platforms for the development of bioactive synthetic compounds. Flavone-8-acetic acid (FAA) and 5,6-dimethylxanthone acetic acid (DMXAA) emerged for their antitumour potential due to the induction of cytokines and consequent rapid haemorrhagic necrosis of murine tumour vasculature, and different series of derivatives have been designed thereafter. Although the promising DMXAA failed in phase III clinical trials because of strict species-specificity, a boost in research came from the recent identification of the stimulator of interferon genes (STING), responsible for supporting tumoural innate immune responses, as a possible biological target. Consequently, in the last decade a renewal of interest for these flavonoid-based structures was noticed, and novel derivatives have been synthesised and evaluated for a deeper understanding of the molecular features needed for affecting human cells. Undoubtedly, these natural-derived molecules deserve further investigation and still appear attractive in an anticancer perspective.
Assuntos
Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ensaios Clínicos Fase III como Assunto , Humanos , Xantenos/farmacologia , Xantonas/farmacologiaRESUMO
Hypoxia severely impedes photodynamic therapy (PDT) efficiency. Worse still, considerable tumor metastasis will occur after PDT. Herein, an organic superoxide radical (O2â- ) nano-photogenerator as a highly effcient type I photosensitizer with robust vascular-disrupting efficiency to combat these thorny issues is designed. Boron difluoride dipyrromethene (BODIPY)-vadimezan conjugate (BDPVDA) is synthesized and enwrapped in electron-rich polymer-brushes methoxy-poly(ethylene glycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) (mPEG- PPDA) to afford nanosized hydrophilic type I photosensitizer (PBV NPs). Owing to outstanding core-shell intermolecular electron transfer between BDPVDA and mPEG-PPDA, remarkable O2â- can be produced by PBV NPs under near-infrared irradiation even in severe hypoxic environment (2% O2 ), thus to accomplish effective hypoxic-tumor elimination. Simultaneously, the efficient ester-bond hydrolysis of BDPVDA in the acidic tumor microenvironment allows vadimezan release from PBV NPs to disrupt vasculature, facilitating the shut-down of metastatic pathways. As a result, PBV NPs will not only be powerful in resolving the paradox between traditional type II PDT and hypoxia, but also successfully prevent tumor metastasis after type I PDT treatment (no secondary-tumors found in 70 days and 100% survival rate), enabling enhancement of existing hypoxic-and-metastatic tumor treatment.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Hipóxia/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Microambiente TumoralRESUMO
Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-ß production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.
Assuntos
Proteínas de Membrana/genética , Síndrome de Sjogren/genética , Animais , Autoanticorpos/sangue , Citocinas/sangue , Citosol/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferons/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Saliva/química , Transdução de Sinais , Síndrome de Sjogren/imunologia , XantonasRESUMO
Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed.
Assuntos
Antineoplásicos/metabolismo , Xantonas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , NF-kappa B/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Óxido Nítrico/metabolismo , Xantonas/farmacologia , Xantonas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.
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High intravenous doses of vitamin C (ascorbic acid) have been reported to benefit cancer patients, but the data are controversial and there is incomplete knowledge of what physiological mechanisms might be involved in any response. Vitamin C is taken up efficiently by cells expressing SVCT2 transporters and since vascular endothelial cells express SVCT2, we explored the hypothesis that administration of high-dose vitamin C (up to 5 g/kg) to mice might affect vascular endothelial function. A single administration of vitamin C to mice induced time- and dose-dependent increases in plasma concentrations of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), a marker for vascular disrupting effects. Responses were comparable to those for the tumor vascular disrupting agents, vadimezan and fosbretabulin. High-dose vitamin C administration decreased tumor serotonin concentrations, consistent with the release of serotonin from platelets and its metabolism to 5-HIAA. High-dose vitamin C also significantly increased the degree of hemorrhagic necrosis in tumors removed after 24 h, and significantly decreased tumor volume after 2 days. However, the effect on tumor growth was temporary. The results support the concept that vitamin C at high dose increases endothelial permeability, allowing platelets to escape and release serotonin. Plasma 5-HIAA concentrations could provide a pharmacodynamic biomarker for vitamin C effects in clinical studies.