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1.
Nat Commun ; 12(1): 5243, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475406

RESUMO

Peroxisome, a special cytoplasmic organelle, possesses one or more kinds of oxidases for hydrogen peroxide (H2O2) production and catalase for H2O2 degradation, which serves as an intracellular H2O2 regulator to degrade toxic peroxides to water. Inspired by this biochemical pathway, we demonstrate the reactive oxygen species (ROS) induced tumor therapy by integrating lactate oxidase (LOx) and catalase (CAT) into Fe3O4 nanoparticle/indocyanine green (ICG) co-loaded hybrid nanogels (designated as FIGs-LC). Based on the O2 redistribution and H2O2 activation by cascading LOx and CAT catalytic metabolic regulation, hydroxyl radical (·OH) and singlet oxygen (1O2) production can be modulated for glutathione (GSH)-activated chemodynamic therapy (CDT) and NIR-triggered photodynamic therapy (PDT), by manipulating the ratio of LOx and CAT to catalyze endogenous lactate to produce H2O2 and further cascade decomposing H2O2 into O2. The regulation reactions of FIGs-LC significantly elevate the intracellular ROS level and cause fatal damage to cancer cells inducing the effective inhibition of tumor growth. Such enzyme complex loaded hybrid nanogel present potential for biomedical ROS regulation, especially for the tumors with different redox state, size, and subcutaneous depth.


Assuntos
Antineoplásicos/farmacologia , Nanogéis/química , Peroxissomos/enzimologia , Fotoquimioterapia/métodos , Animais , Antineoplásicos/química , Catalase/química , Catalase/metabolismo , Catálise , Linhagem Celular Tumoral , Óxido Ferroso-Férrico/química , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Verde de Indocianina/química , Camundongos , Oxigenases de Função Mista/química , Oxigenases de Função Mista/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
2.
Anticancer Res ; 41(9): 4505-4513, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475076

RESUMO

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Angiografia por Tomografia Computadorizada , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
3.
Molecules ; 26(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34443544

RESUMO

Naturally occurring pentacyclic triterpenoid oleanolic acid (OA) serves as a good scaffold for additional modifications to achieve synthetic derivatives. Therefore, a large number of triterpenoids have been synthetically modified in order to increase their bioactivity and their protective or therapeutic effects. Moreover, attempts were performed to conjugate synthetic triterpenoids with non-steroidal anti-inflammatory drugs (NSAIDs) or other functional groups. Among hundreds of synthesized triterpenoids, still the most promising is 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which reached clinical trials level of investigations. The new group of synthetic triterpenoids are OA oximes. The most active among them is 3-hydroxyiminoolean-12-en-28-oic acid morpholide, which additionally improves the anti-cancer activity of standard NSAIDs. While targeting the Nrf2 and NF-κB signaling pathways is the main mechanism of synthetic OA derivatives' anti-inflammatory and anti-cancer activity, most of these compounds exhibit multifunctional activity, and affect cross-talk within the cellular signaling network. This short review updates the earlier data and describes the new OA derivatives and their conjugates in the context of modification of signaling pathways involved in inflammation and cell survival and subsequently in cancer development.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Ácido Oleanólico/farmacologia , Animais , Humanos , Simulação de Acoplamento Molecular , Ácido Oleanólico/química , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
4.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360896

RESUMO

Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFßR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFßR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFßR inhibitor-based clinical trials on pancreatic cancer are reviewed.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
5.
Nutrients ; 13(8)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34444860

RESUMO

Cyclophosphamide (CTX) is widely applied in cancer treatment. However, the outcome is often compromised by lymphopenia, myelosuppression, and gut dysbiosis. Here, we used jujube powder to enhance CTX efficiency through nurturing gut microbiota in order to facilitate favorable metabolisms. It was observed that the oral administration of jujube powder enriched CD8+ T cells in mouse MC38 colon tumor microenvironment and increased the diversity of gut microbiota and the abundance of Bifidobacteriales, which is helpful to the production of butyrate in the cecum content. The application of jujube powder also stimulated the production of white blood cells, especially CD8+ T cells in peripheral and bone marrow, while inhibiting the growth of eosinophils in peripheral blood and the production of IL-7 and GM-CSF in serum. All these are conductive to the significant inhibition of the tumor growth, suggesting the high potential of nurturing gut microbiota with natural products for improving the efficiency of chemotherapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ciclofosfamida/farmacologia , Frutas , Ziziphus , Animais , Medula Óssea/metabolismo , Terapia Combinada , Modelos Animais de Doenças , Eosinofilia , Microbioma Gastrointestinal/efeitos dos fármacos , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Camundongos , Pós , Microambiente Tumoral/efeitos dos fármacos
6.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382406

RESUMO

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Assuntos
Antineoplásicos/química , Monóxido de Carbono/química , Compostos de Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/metabolismo , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Imunoterapia/métodos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias Experimentais , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
7.
ACS Appl Mater Interfaces ; 13(33): 39934-39948, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34396771

RESUMO

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Glutationa/química , Indóis/química , Nanopartículas/química , Oxaliplatina/química , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Glutationa/metabolismo , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/efeitos da radiação , Imunoterapia , Indóis/farmacocinética , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Oxaliplatina/farmacocinética , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Polietilenoglicóis/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
8.
Theranostics ; 11(16): 7735-7754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335961

RESUMO

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Compostos Organometálicos/farmacologia , Osteoclastos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Neoplasias Ósseas , Osso e Ossos/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fluordesoxiglucose F18/farmacologia , Humanos , Cadeias alfa de Integrinas/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Mieloma Múltiplo/metabolismo , Compostos Organometálicos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteólise/patologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Anticancer Res ; 41(7): 3247-3252, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230118

RESUMO

Cancer immunotherapy is an evolving field of research. Cytokines have been conceptualized as an anticancer therapy for longer than most other cancer immunotherapy modalities. Yet, to date, only two cytokines are FDA-approved: IFN-α and IL-2. Despite the initial breakthrough, both agents have been superseded by other, more efficacious agents such as immune checkpoint inhibitors. Several issues persist with cytokine-based cancer therapies; these are broadly categorised into a) high toxicity and b) low efficacy. Despite the only moderate benefits with early cytokine-based cancer therapies, advances in molecular engineering, genomics, and molecular analysis hold promise to optimise and reinstate cytokine-based therapies in future clinical practice. This review considers five important concepts for the successful clinical application of cytokine-based cancer therapies including: (i) improving pharmacokinetics and pharmacodynamics, (ii) improving local administration strategies, (iii) understanding context-dependent interactions in the tumour-microenvironment, (iv) elucidating the role of genetic polymorphisms, and (v) optimising combination therapies. IL-10 has been the focus of attention in recent years and is discussed herein as an example.


Assuntos
Citocinas/farmacologia , Citocinas/uso terapêutico , Interleucina-10/farmacologia , Interleucina-10/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia , Animais , Humanos , Imunoterapia/métodos , Polimorfismo Genético/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
10.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206957

RESUMO

In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or "sanctuary" where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular "crosstalk" with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia-bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia.


Assuntos
Leucemia/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Humanos , Leucemia/patologia , Transdução de Sinais
11.
Nat Commun ; 12(1): 4558, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315904

RESUMO

Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.


Assuntos
Neoplasias Ósseas/complicações , Dor do Câncer/etiologia , Dor do Câncer/imunologia , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Analgésicos/farmacologia , Animais , Neoplasias Ósseas/sangue , Dor do Câncer/sangue , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/patologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Proteínas de Homeodomínio/metabolismo , Hiperalgesia/complicações , Interferons/sangue , Interferons/metabolismo , Masculino , Neoplasias Mamárias Animais/complicações , Proteínas de Membrana/agonistas , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Xantonas/farmacologia
12.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199510

RESUMO

During aggressive cancer progression, cancer cells adapt to unique microenvironments by withstanding various cellular stresses, including endoplasmic reticulum (ER) stress. However, the mechanism whereby cancer cells overcome the ER stress to survive remains to be elucidated. Herein, we demonstrated that microtubule acetylation in cancer cells grown on a stiff matrix promotes cancer progression by preventing excessive ER stress. Downregulation of microtubule acetylation using shRNA or CRSIPR/Cas9 techniques targeting ATAT1, which encodes α-tubulin N-acetyltransferase (αTAT1), resulted in the upregulation of ER stress markers, changes in ER morphology, and enhanced tunicamycin-induced UPR signaling in cancer cells. A set of genes involved in cancer progression, especially focal adhesion genes, were downregulated in both ATAT1-knockout and tunicamycin-treated cells, whereas ATAT1 overexpression restored the gene expression inhibited by tunicamycin. Finally, the expression of ATAT1 and ER stress marker genes were negatively correlated in various breast cancer types. Taken together, our results suggest that disruption of microtubule acetylation is a potent therapeutic tool for preventing breast cancer progression through the upregulation of ER stress. Moreover, ATAT1 and ER stress marker genes may be useful diagnostic markers in various breast cancer types.


Assuntos
Acetiltransferases/genética , Neoplasias da Mama/genética , Estresse do Retículo Endoplasmático/genética , Proteínas dos Microtúbulos/genética , Tunicamicina/farmacologia , Acetilação/efeitos dos fármacos , Acetiltransferases/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas dos Microtúbulos/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Microambiente Tumoral/efeitos dos fármacos
13.
Nat Commun ; 12(1): 4405, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285232

RESUMO

Stimulator of interferon genes (STING) promotes anti-tumour immunity by linking innate and adaptive immunity, but it remains unclear how intratumoural treatment with STING agonists yields anti-tumour effects. Here we demonstrate that intratumoural injection of the STING agonist cGAMP induces strong, rapid, and selective apoptosis of tumour endothelial cells (ECs) in implanted LLC tumour, melanoma and breast tumour, but not in spontaneous breast cancer and melanoma. In both implanted and spontaneous tumours, cGAMP greatly increases TNFα from tumour-associated myeloid cells. However, compared to spontaneous tumour ECs, implanted tumour ECs are more vulnerable to TNFα-TNFR1 signalling-mediated apoptosis, which promotes effective anti-tumour activity. The spontaneous tumour's refractoriness to cGAMP is abolished by co-treatment with AKT 1/2 inhibitor (AKTi). Combined treatment with cGAMP and AKTi induces extensive tumour EC apoptosis, leading to extensive tumour apoptosis and marked growth suppression of the spontaneous tumour. These findings propose an advanced avenue for treating primary tumours that are refractory to single STING agonist therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Membrana/agonistas , Neoplasias/tratamento farmacológico , Nucleotídeos Cíclicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunidade Inata/efeitos dos fármacos , Injeções Intralesionais , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/patologia , Nucleotídeos Cíclicos/uso terapêutico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo
14.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201298

RESUMO

The tumor microenvironment (TME) is a heterogenous assemblage of malignant and non-malignant cells, including infiltrating immune cells and other stromal cells, together with extracellular matrix and a variety of soluble factors. This complex and dynamic milieu strongly affects tumor differentiation, progression, immune evasion, and response to therapy, thus being an important therapeutic target. The phenotypic and functional features of the various cell types present in the TME are largely dependent on their ability to adopt different metabolic programs. Hence, modulating the metabolism of the cells in the TME, and their metabolic crosstalk, has emerged as a promising strategy in the context of anticancer therapies. Natural compounds offer an attractive tool in this respect as their multiple biological activities can potentially be harnessed to '(re)-educate' TME cells towards antitumoral roles. The present review discusses how natural compounds shape the metabolism of stromal cells in the TME and how this may impact tumor development and progression.


Assuntos
Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Progressão da Doença , Humanos , Neoplasias/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo
15.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201944

RESUMO

Photodynamic therapy (PDT) as a safe, non-invasive modality for cancer therapy, in which the low oxygen and high glutathione in the tumor microenvironment reduces therapeutic efficiency. In order to overcome these problems, we prepared a supramolecular photosensitive system of O2-Cu/ZIF-8@ZIF-8@WP6-MB (OCZWM), which was loaded with oxygen to increase the oxygen concentration in the tumor microenvironment, and the Cu2+ in the system reacted with glutathione (GSH) to reduce the GSH concentration to generate Cu+. It is worth noting that the generated Cu+ can produce the Fenton reaction, thus realizing the combination therapy of PDT and chemodynamic therapy (CDT) to achieve the purpose of significantly improving the anti-cancer efficiency.


Assuntos
Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes , Microambiente Tumoral/efeitos dos fármacos , Células Hep G2 , Humanos , Azul de Metileno/química , Neoplasias/metabolismo , Neoplasias/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Compostos de Amônio Quaternário/química
16.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204668

RESUMO

Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Portadores de Fármacos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias/tratamento farmacológico , Poloxâmero/química , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Polietilenoglicóis/metabolismo , Polímeros/química , Polipropilenos/química , Polipropilenos/farmacologia , Propilenoglicóis/metabolismo , Microambiente Tumoral/efeitos dos fármacos
17.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298999

RESUMO

The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Cisplatino/uso terapêutico , Glicólise/efeitos dos fármacos , Humanos , Cinurenina/metabolismo , NAD/metabolismo , Oxirredução , Poli(ADP-Ribose) Polimerase-1/metabolismo , Sirtuínas/metabolismo
18.
Int J Biol Macromol ; 185: 664-678, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34224755

RESUMO

Nowadays, the targeted imaging probe and drug delivery systems are the novel breakthrough area in the nanomedicine and treatment of various diseases. Conjugation of monoclonal antibodies and their fragments on nanoparticles (NPs) have a remarkable impact on personalized medicine, such that it provides specific internalization and accumulation in the tumor microenvironment. Targeted imaging and early detection of cancer is presumably the strong participant to a diminution in mortality and recurrence of cancer disease that will be the next generation of the imaging device in clinical application. These intelligent delivery systems can deliver therapeutic agents that target cancerous tissue with minimal side effects and a wide therapeutic window. Overall, the linkage between the antibody and NPs is a critical subject and requires precise design and development. The attachment of antibody nanoconjugates (Ab-NCs) on the antigen surface shouldn't affect the function of the antibody-antigen binding. Also, the stability of the antibody nanoconjugates in blood circulation is concerned to avoid the release of drug in non-targeted regions and the possible for specific toxicity while disposal to the desired site. Here, we update the recent progress of Ab-NCs to improve early detection and cancer therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/imunologia , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Detecção Precoce de Câncer , Humanos , Nanoconjugados , Neoplasias/imunologia , Patologia Molecular , Medicina de Precisão , Microambiente Tumoral/efeitos dos fármacos
19.
Int J Nanomedicine ; 16: 4559-4577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267513

RESUMO

Purpose: Reactive oxygen species (ROS) are a group of signaling biomolecules that play important roles in the cell cycle. When intracellular ROS homeostasis is disrupted, it can induce cellular necrosis and apoptosis. It is desirable to effectively cascade-amplifying ROS generation and weaken antioxidant defense for disrupting ROS homeostasis in tumor microenvironment (TME), which has been recognized as a novel and ideal antitumor strategy. Multifunctional nanozymes are highly promising agents for ROS-mediated therapy. Methods: This study constructed a novel theranostic nanoagent based on PEG@Cu2-xS@Ce6 nanozymes (PCCNs) through a facile one-step hydrothermal method. We systematically investigated the photodynamic therapy (PDT)/photothermal therapy (PTT) properties, catalytic therapy (CTT) and glutathione (GSH) depletion activities of PCCNs, antitumor efficacy induced by PCCNs in vitro and in vivo. Results: PCCNs generate singlet oxygen (1O2) with laser (660 nm) irradiation and use catalytic reactions to produce hydroxyl radical (•OH). Moreover, PCCNs show the high photothermal performance under NIR II 1064-nm laser irradiation, which can enhance CTT/PDT efficiencies to increase ROS generation. The properties of O2 evolution and GSH consumption of PCCNs achieve hypoxia-relieved PDT and destroy cellular antioxidant defense system respectively. The excellent antitumor efficacy in 4T1 tumor-bearing mice of PCCNs is achieved through disrupting ROS homeostasis-involved therapy under the guidance of photothermal/photoacoustic imaging. Conclusion: Our study provides a proof of concept of "all-in-one" nanozymes to eliminate tumors via disrupting ROS homeostasis.


Assuntos
Homeostase/efeitos dos fármacos , Hipertermia Induzida/métodos , Raios Infravermelhos , Nanomedicina/métodos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Catálise , Linhagem Celular Tumoral , Cério/química , Cobre/química , Glutationa/metabolismo , Humanos , Camundongos , Polietilenoglicóis/química , Sulfetos/química
20.
Life Sci ; 280: 119750, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171378

RESUMO

The tumor microenvironment (TME) constitutes multiple cell types including cancerous and non-cancerous cells. The intercellular communication between these cells through TME derived exosomes may either enhance or suppress the tumorigenic processes. The tumor-derived exosomes could convert an anti-tumor environment into a pro-tumor environment by inducing the differentiation of stromal cells into tumor-associated cells. The exosomes from tumor-associated stromal cells reciprocally trigger epithelial-to-mesenchymal transition (EMT) in tumor cells, which impose therapeutic resistance and metastasis. It is well known that these exosomes contain the signals of EMT, but how these signals execute chemoresistance and metastasis in tumors remains elusive. Understanding the significance and molecular signatures of exosomes transmitting EMT signals would aid in developing appropriate methods of inhibiting them. In this review, we focus on molecular signatures of exosomes that shuttle between cancer cells and their stromal populations in TME to explicate their impact on therapeutic resistance and metastasis through EMT. Especially Wnt signaling is found to be involved in multiple ways of exosomal transport and hence we decipher the biomolecules of Wnt signaling trafficked through exosomes and their potential in serving as therapeutic targets.


Assuntos
Transição Epitelial-Mesenquimal , Exossomos/patologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Comunicação Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Humanos , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
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