RESUMO
Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.
Assuntos
Ferro , Microambiente Tumoral , Animais , Ferro/metabolismo , Camundongos , Microambiente Tumoral/imunologia , Humanos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/imunologia , Camundongos Endogâmicos C57BL , Lipocalina-2/metabolismo , Lipocalina-2/imunologia , Feminino , Simbiose/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Ativação de Macrófagos/imunologia , Camundongos KnockoutRESUMO
Five osmium(II) polypyridyl complexes of the general formula [Os(4,7-diphenyl-1,10-phenanthroline)2 L]2+ were synthesized as photosensitizers for photodynamic therapy by varying the nature of the ligand L. Thanks to the pronounced π-extended structure of the ligands and the heavy atom effect provided by the osmium center, these complexes exhibit a high absorption in the near-infrared (NIR) region (up to 740â nm), unlike related ruthenium complexes. This led to a promising phototoxicity in vitro against cancer cells cultured as 2D cell layers but also in multicellular tumor spheroids upon irradiation at 740â nm. The complex [Os(4,7-diphenyl-1,10-phenanthroline)2 (2,2'-bipyridine)]2+ was found to be the most efficient against various cancer cell lines, with high phototoxicity indexes. Experiments on CT26 tumor-bearing BALB/c mice also indicate that the OsII complexes could significantly reduce tumor growth following 740â nm laser irradiation. The high phototoxicity in the biological window of this structurally simple complex makes it a promising photosensitizer for cancer treatment.
Assuntos
Complexos de Coordenação , Neoplasias , Fotoquimioterapia , Rutênio , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Osmio/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Complexos de Coordenação/química , Neoplasias/tratamento farmacológico , Rutênio/farmacologia , Rutênio/químicaRESUMO
The general perception of viruses is that they are small in terms of size and genome, and that they hijack the host machinery to glycosylate their capsid. Giant viruses subvert all these concepts: their particles are not small, and their genome is more complex than that of some bacteria. Regarding glycosylation, this concept has been already challenged by the finding that Chloroviruses have an autonomous glycosylation machinery that produces oligosaccharides similar in size to those of small viruses (6-12 units), albeit different in structure compared to the viral counterparts. We report herein that Mimivirus possesses a glycocalyx made of two different polysaccharides, now challenging the concept that all viruses coat their capsids with oligosaccharides of discrete size. This discovery contradicts the paradigm that such macromolecules are absent in viruses, blurring the boundaries between giant viruses and the cellular world and opening new avenues in the field of viral glycobiology.
Assuntos
Mimiviridae/metabolismo , Polissacarídeos/biossíntese , Glicosilação , Mimiviridae/química , Polissacarídeos/químicaRESUMO
On the 14-15th November 2019, the first workshop on Metals in Medicine took place in Paris at Chimie ParisTech, PSL University. Organised with the aim of having invited speakers share their experience in bringing metal-based drugs to (pre-)clinical trials, this event gathered 135 attendees from six continents to Paris. A special collection on this event has now been published in ChemBioChem, combining more than 20 articles on different topics related to metals in medicine.
Assuntos
Química Bioinorgânica , Congressos como Assunto , Desenvolvimento de Medicamentos , Metais Pesados/uso terapêutico , Humanos , Metais Pesados/química , Neoplasias/tratamento farmacológico , Paris , Pesquisa Translacional BiomédicaRESUMO
Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, [Ru(DIP)2(sq)](PF6) (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinized in vitro and in vivo, and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer.
Assuntos
Antineoplásicos/química , Antineoplásicos/metabolismo , Quinonas/química , Quinonas/metabolismo , Rutênio/química , Rutênio/metabolismo , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Feminino , Células HeLa , Humanos , Ligantes , Camundongos , Camundongos Nus , Oxirredução/efeitos dos fármacos , Quinonas/farmacologia , Rutênio/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Four novel monocationic Ru(II) polypyridyl complexes were synthesized with the general formula [Ru(DIP)2flv]X, where DIP is 4,7-diphenyl-1,10-phenanthroline, flv stands for the flavonoid ligand (5-hydroxyflavone in [Ru(DIP)2(5-OHF)](PF6), genistein in [Ru(DIP)2(gen)](PF6), chrysin in [Ru(DIP)2(chr)](OTf), and morin in [Ru(DIP)2(mor)](OTf)), and X is the counterion, PF6-, and OTf Ì (triflate, CF3SO3Ì ), respectively. Following the chemical characterization of the complexes by 1H and 13C NMR, mass spectrometry, and elemental analysis, their cytotoxicity was tested against several cancer cell lines. The most promising complex, [Ru(DIP)2(gen)](PF6), was further investigated for its biological activity. Metabolic studies revealed that this complex severely impaired mitochondrial respiration and glycolysis processes, contrary to its precursor, Ru(DIP)2Cl2, which showed a prominent effect only on the mitochondrial respiration. In addition, its preferential accumulation in MDA-MB-435S cells (a human melanoma cell line previously described as mammary gland/breast; derived from metastatic site: pleural effusion), which are used for the study of metastasis, explained the better activity in this cell line compared to MCF-7 (human, ductal carcinoma).
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Flavonoides/farmacologia , Piridinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/síntese química , Glicólise/efeitos dos fármacos , Humanos , Ligantes , Mitocôndrias/efeitos dos fármacos , Piridinas/síntese química , Rutênio/químicaRESUMO
Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP)2 (sq)](PF6 ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)2 (mal)](PF6 ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)2 (mal)](PF6 ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP)2 (mal)](PF6 ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Pironas/farmacologia , Rutênio/química , Antineoplásicos/química , Cisplatino/química , Complexos de Coordenação/química , Células HeLa , Humanos , Ligantes , Estrutura Molecular , Pironas/química , Rutênio/farmacologiaRESUMO
Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq ([Ru(DIP)2(sq)](PF6) (DIP, 4,7-diphenyl-1,10-phenanthroline; sq, semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) study that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP)2 core. In more detail, we chose catechols carrying either an electron-donating group (EDG) or an electron-withdrawing group (EWG) and investigated the physicochemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep-red positively charged complexes 1-4 in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes, which carry an EWG-substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1-6 led to the conclusion that the difference in their physicochemical properties has a strong impact on their biological activity. Thus, complexes 1-4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound in the series and was selected for a more in depth biological investigation. Apart from its remarkably high cytotoxicity (IC50 = 0.07-0.7 µM in different cancerous cell lines), complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e., nucleus, lysosomes, mitochondria, and cytoplasm) is extremely advantageous in the search for a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research. It is noteworthy that a preliminary biodistribution study on healthy mice demonstrated the suitability of complex 1 for further in vivo studies.
RESUMO
Poor aqueous solubility is one of the recurrent drawbacks of many compounds in medicinal chemistry. To overcome this limitation, the dilution of drug candidates from stock solutions of an organic solvent is common practice. However, the precise characterisation of these compounds in aqueous solutions is often neglected, leading to some uncertainties regarding the nature of the actual active species. In this communication, we demonstrate that two ruthenium complexes previously reported by our group for their chemotherapeutic potential against cancer, namely [Ru(DIP)2 (sq)](PF6 ) and [Ru(DIP)2 (3-methoxysq)](PF6 ), where DIP is 4,7-diphenyl-1,10-phenanthroline, sq=semiquinonate and 3-methoxysq=3-methoxysemiquinonate, form colloids in water-DMSO (1 % v/v) mixtures that are invisible to the naked eyes. [Ru(DIP)2 (3-methoxysq)](PF6 ) was found to form a highly stable and monodispersed colloid with nanoaggregates of â¼25â nm. In contrast, [Ru(DIP)2 (sq)](PF6 ) was found to form large reticulates of mostly spherical aggregates which size was found to increase over time. The difference in size and shape distribution of drug candidates is of tremendous significance as the study of their biological activity might be severely affected. Overall, we strongly believe that these observations should be taken into account by the scientific community working on the development of metal-based drugs with poor water solubility.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Neoplasias/tratamento farmacológico , Rutênio/química , Rutênio/uso terapêutico , Água/química , Complexos de Coordenação/química , Humanos , Microscopia Eletrônica de Transmissão , Estrutura MolecularRESUMO
Due to the increasing impact of cancer on worldwide mortality, more and more attention is being devoted to the investigation of novel anticancer strategies. Among these, chemotherapy plays a key role in fighting cancer. This explains the increasing engagement of both the pharmaceutical industry and academia towards the discovery of new chemotherapeutic agents. In recent years, metal-based drugs have attracted much attention due to their atypical physico-chemical properties compared to organic molecules. After the approval of cisplatin as a chemotherapeutic agent in 1978, several types of metal-based drugs have been explored. Among them, Ru-based anticancer drug candidates have become a central subject in this research field. However, most of the Ru-based compounds investigated over the last two decades express their cytotoxicity with a mechanism of action involving, among others, a ligand-exchange mechanism. In this Review, we give a complete overview of a specific class of antiproliferative ruthenium complexes, namely coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes. This implies that the cytotoxicity observed comes from the entire complex and not from ligand-exchange. In this Review, we present monomeric and dimeric Ru(ii) polypyridyl complexes, which have been found to be toxic to cancer cells. More specifically, monomeric Ru(ii) polypyridyl complexes are analysed considering their direct interaction or not with DNA as the cause of cell death, while dimeric Ru(ii) polypyridyl complexes are classified according to their biological targets. Very importantly, the cellular targets of these complexes are discussed in detail. Indeed, several targets were identified and different mechanisms of action were suggested.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Neoplasias/tratamento farmacológico , Piridinas/farmacologia , Rutênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Humanos , Neoplasias/patologia , Piridinas/química , Rutênio/químicaRESUMO
The giant virus Mimivirus encodes an autonomous glycosylation system that is thought to be responsible for the formation of complex and unusual glycans composing the fibers surrounding its icosahedral capsid, including the dideoxyhexose viosamine. Previous studies have identified a gene cluster in the virus genome, encoding enzymes involved in nucleotide-sugar production and glycan formation, but the functional characterization of these enzymes and the full identification of the glycans found in viral fibers remain incomplete. Because viosamine is typically found in acylated forms, we suspected that one of the genes might encode an acyltransferase, providing directions to our functional annotations. Bioinformatic analyses indicated that the L142 protein contains an N-terminal acyltransferase domain and a predicted C-terminal glycosyltransferase. Sequence analysis of the structural model of the L142 N-terminal domain indicated significant homology with some characterized sugar acetyltransferases that modify the C-4 amino group in the bacillosamine or perosamine biosynthetic pathways. Using mass spectrometry and NMR analyses, we confirmed that the L142 N-terminal domain is a sugar acetyltransferase, catalyzing the transfer of an acetyl moiety from acetyl-CoA to the C-4 amino group of UDP-d-viosamine. The presence of acetylated viosamine in vivo has also been confirmed on the glycosylated viral fibers, using GC-MS and NMR. This study represents the first report of a virally encoded sugar acetyltransferase.