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1.
Proc Natl Acad Sci U S A ; 121(15): e2321116121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38557176

RESUMO

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Animais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Quimioterapia Combinada , Linhagem Celular Tumoral
2.
Cancer Rep (Hoboken) ; 7(4): e2074, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38627904

RESUMO

BACKGROUND: Iatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy-induced cognitive neurotoxicity is clinically referred to as Chemotherapy-induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline-DOX) and Cyclophosphamide (Alkylating Cytophosphane-CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function. AIM: This study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide. METHODS AND RESULTS: Doxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex-I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT-PCR methods, respectively. Prism-V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose-dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function. CONCLUSION: This is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy-induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.


Assuntos
Neoplasias da Mama , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transtornos dos Movimentos , Humanos , Feminino , Ciclofosfamida/efeitos adversos , Antraciclinas/uso terapêutico , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Antibióticos Antineoplásicos , Doxorrubicina/farmacologia , Neoplasias da Mama/patologia , Transtornos dos Movimentos/tratamento farmacológico
3.
Nano Lett ; 24(15): 4354-4361, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38563599

RESUMO

The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Nanopartículas , Humanos , Feminino , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Microambiente Tumoral
4.
J Nanobiotechnology ; 22(1): 184, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622644

RESUMO

Despite the advent of numerous targeted therapies in clinical practice, anthracyclines, including doxorubicin (DOX), continue to play a pivotal role in breast cancer (BC) treatment. DOX directly disrupts DNA replication, demonstrating remarkable efficacy against BC cells. However, its non-specificity toward cancer cells leads to significant side effects, limiting its clinical utility. Interestingly, DOX can also enhance the antitumor immune response by promoting immunogenic cell death in BC cells, thereby facilitating the presentation of tumor antigens to the adaptive immune system. However, the generation of an adaptive immune response involves highly proliferative processes, which may be adversely affected by DOX-induced cytotoxicity. Therefore, understanding the impact of DOX on dividing T cells becomes crucial, to deepen our understanding and potentially devise strategies to shield anti-tumor immunity from DOX-induced toxicity. Our investigation focused on studying DOX uptake and its effects on human lymphocytes. We collected lymphocytes from healthy donors and BC patients undergoing neoadjuvant chemotherapy (NAC). Notably, patient-derived peripheral blood mononuclear cells (PBMC) promptly internalized DOX when incubated in vitro or isolated immediately after NAC. These DOX-treated PBMCs exhibited significant proliferative impairment compared to untreated cells or those isolated before treatment initiation. Intriguingly, among diverse lymphocyte sub-populations, CD8 + T cells exhibited the highest uptake of DOX. To address this concern, we explored a novel DOX formulation encapsulated in ferritin nanocages (FerOX). FerOX specifically targets tumors and effectively eradicates BC both in vitro and in vivo. Remarkably, only T cells treated with FerOX exhibited reduced DOX internalization, potentially minimizing cytotoxic effects on adaptive immunity.Our findings underscore the importance of optimizing DOX delivery to enhance its antitumor efficacy while minimizing adverse effects, highlighting the pivotal role played by FerOX in mitigating DOX-induced toxicity towards T-cells, thereby positioning it as a promising DOX formulation. This study contributes valuable insights to modern cancer therapy and immunomodulation.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Leucócitos Mononucleares , Terapia Neoadjuvante , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Antineoplásicos/farmacologia , Linhagem Celular Tumoral
5.
Commun Biol ; 7(1): 426, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589567

RESUMO

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.


Assuntos
Hidrazinas , Neoplasias Renais , Triazóis , Tumor de Wilms , Humanos , 60611 , Transporte Ativo do Núcleo Celular , Carioferinas/genética , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Linhagem Celular Tumoral , Apoptose , Recidiva Local de Neoplasia , Doxorrubicina/farmacologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Ciclo Celular/metabolismo
6.
Oncotarget ; 15: 248-254, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38588464

RESUMO

Acute myeloid leukemia (AML) is characterized by the rapid proliferation of mutagenic hematopoietic progenitors in the bone marrow. Conventional therapies include chemotherapy and bone marrow stem cell transplantation; however, they are often associated with poor prognosis. Notably, growth hormone-releasing hormone (GHRH) receptor antagonist MIA-602 has been shown to impede the growth of various human cancer cell lines, including AML. This investigation examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant AML cell lines, KG-1A, U-937, and K-562. The in vitro results revealed a significant reduction in cell viability for all treated wild-type cells. Doxorubicin-resistant clones were similarly susceptible to MIA-602 as the wild-type counterpart. Our in vivo experiment of xenografted nude mice with Doxorubicin-resistant K-562 revealed a reduction in tumor volume with MIA-602 treatment compared to control. Our study demonstrates that these three AML cell lines, and their Doxorubicin-resistant clones, are susceptible to GHRH antagonist MIA-602.


Assuntos
Hormônio Liberador de Hormônio do Crescimento , Leucemia Mieloide Aguda , Sermorelina/análogos & derivados , Camundongos , Animais , Humanos , Camundongos Nus , Proliferação de Células , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Doxorrubicina/farmacologia
7.
Med Oncol ; 41(5): 111, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592504

RESUMO

The use of doxorubicin (Dox) in the treatment of breast cancer negatively affects the intestines and other tissues. Many studies have proven that probiotics and vitamin D3 have antitumor and intestinal tissue-protecting properties. To achieve effectiveness and minimize side effects, the current study aims to administer Dox together with probiotics (Lactobacillus acidophilus and Lactobacillus casei) and vitamin D3. Forty-two female BALB/c inbred mice were divided into six groups: Group 1 (Control), Group 2 (Dox), Group 3 (Dox and probiotics), Group 4 (Dox and vitamin D3), Group 5 (Dox, probiotics, and vitamin D3), and Group 6 (probiotics and vitamin D3). The 4T1 mouse carcinoma cell line was injected into the mammary fat pad of each mouse. Gene expression was examined using quantitative real-time PCR. The treated groups (except group 6) showed significantly reduced tumor volume and weight compared to the control group (P < 0.05, P < 0.01). Probiotics/vitamin D3 with Dox reduced chemotherapy toxicity and a combination of supplements had a significant protective effect against Dox (P < 0.05, 0.01, 0.001). The treated groups (except 6) had significantly higher expression of Bax/Caspase 3 genes and lower expression of Bcl-2 genes than the control group (P < 0.05, 0.01). Coadministration of Dox with probiotics and vitamin D3 showed promising results in reducing tumor size, protecting intestinal tissue and influencing gene expression, suggesting a strategy to enhance the effectiveness of breast cancer treatment while reducing side effects.


Assuntos
Lacticaseibacillus casei , Neoplasias , Probióticos , Feminino , Animais , Camundongos , Lactobacillus acidophilus , Doxorrubicina/farmacologia , Probióticos/farmacologia , Modelos Animais de Doenças , Colecalciferol/farmacologia , Camundongos Endogâmicos BALB C
8.
J Nanobiotechnology ; 22(1): 168, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38610015

RESUMO

BACKGROUND: Oral cancer is the most common malignant tumor of the head and neck, and 90% of cases are oral squamous cell carcinoma (OSCC). Chemotherapy is an important component of comprehensive treatment for OSCC. However, the clinical treatment effect of chemotherapy drugs, such as doxorubicin (DOX), is limited due to the lack of tumor targeting and rapid clearance by the immune system. Thus, based on the tumor-targeting and immune evasion abilities of macrophages, macrophage membrane-encapsulated poly(methyl vinyl ether alt maleic anhydride)-phenylboronic acid-doxorubicin nanoparticles (MM@PMVEMA-PBA-DOX NPs), briefly as MM@DOX NPs, were designed to target OSCC. The boronate ester bonds between PBA and DOX responded to the low pH value in the tumor microenvironment, selectively releasing the loaded DOX. RESULTS: The results showed that MM@DOX NPs exhibited uniform particle size and typical core-shell structure. As the pH decreased from 7.4 to 5.5, drug release increased from 14 to 21%. The in vitro targeting ability, immune evasion ability, and cytotoxicity of MM@DOX NPs were verified in HN6 and SCC15 cell lines. Compared to free DOX, flow cytometry and fluorescence images demonstrated higher uptake of MM@DOX NPs by tumor cells and lower uptake by macrophages. Cell toxicity and live/dead staining experiments showed that MM@DOX NPs exhibited stronger in vitro antitumor effects than free DOX. The targeting and therapeutic effects were further confirmed in vivo. Based on in vivo biodistribution of the nanoparticles, the accumulation of MM@DOX NPs at the tumor site was increased. The pharmacokinetic results demonstrated a longer half-life of 9.26 h for MM@DOX NPs compared to 1.94 h for free DOX. Moreover, MM@DOX NPs exhibited stronger tumor suppression effects in HN6 tumor-bearing mice and good biocompatibility. CONCLUSIONS: Therefore, MM@DOX NPs is a safe and efficient therapeutic platform for OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Animais , Camundongos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias Bucais/tratamento farmacológico , Distribuição Tecidual , Macrófagos , Doxorrubicina/farmacologia , Concentração de Íons de Hidrogênio , Microambiente Tumoral
9.
Oncol Res ; 32(4): 769-784, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38560569

RESUMO

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect. To improve the treatment efficacy, we developed Pluronic P123 (P123)-based polymeric micelles dually decorated with alendronate (ALN) and cancer-specific phage protein DMPGTVLP (DP-8) for targeted drug delivery to breast cancer bone metastases. Doxorubicin (DOX) was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity (3.44%). The DOX-loaded polymeric micelles were spherical, 123 nm in diameter on average, and exhibited a narrow size distribution. The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release. The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells. Rapid binding of the micelles to hydroxyapatite (HA) microparticles indicated their high affinity for bone. P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model. In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity. In conclusion, our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Neoplasias da Mama , Poloxaleno , Humanos , Feminino , Micelas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ligantes , Qualidade de Vida , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Polímeros/química , Polímeros/uso terapêutico , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias Ósseas/tratamento farmacológico , Alendronato/farmacologia , Alendronato/química , Alendronato/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico
10.
Commun Biol ; 7(1): 402, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565675

RESUMO

Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.


Assuntos
Glomerulosclerose Segmentar e Focal , Podócitos , Animais , Camundongos , Doxorrubicina/farmacologia , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/prevenção & controle , Camundongos Knockout , Podócitos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Esclerose/metabolismo , Esclerose/patologia
11.
Int J Biol Macromol ; 265(Pt 1): 130901, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38490383

RESUMO

This study introduces a starch/PVA/g-C3N4 nanocarrier hydrogel for pH-sensitive DOX delivery in breast cancer. DOX was loaded into the nanocarrier with 44.75 % loading efficiency and 88 % Entrapment Efficiency. The release of DOX from the starch/PVA/g-C3N4 hydrogel was pH-sensitive: DOX was released faster in the acidic environment pertinent to cancer tumors (with a pH level of 5.4) than in the surrounding regular tissue environment carrying a more neutral environment (pH 7.4). The release kinetics analysis, encompassing zero-order, first-order, Higuchi, and Korsmeyer-Peppas models, revealed significant fitting with the Higuchi model at both pH 5.4 (R2 = 0.99, K = 9.89) and pH 7.4 (R2 = 0.99, K = 5.70) levels. Finally, we found that hydrogel was less damaging to healthy cells and more specific to apoptotic cells than the drug's free form. The starch/PVA/g-C3N4 hydrogel had low toxicity for both normal cells and breast cancer cells, whereas DOX loaded into the starch/PVA/g-C3N4 hydrogel had higher toxicity for cancer cells than the DOX-only control samples, and led to specific high apoptosis for cancer cells. The study suggests that DOX can be loaded into a starch/PVA/g-C3N4 hydrogel to improve the specificity of the drug's release in cancer tumors or in vitro breast cancer cells.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Hidrogéis/uso terapêutico , Amido/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Concentração de Íons de Hidrogênio , Portadores de Fármacos/uso terapêutico
12.
J Colloid Interface Sci ; 665: 329-344, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38531278

RESUMO

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy-and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.


Assuntos
Neoplasias , Polímeros , Nanogéis , Polímeros/química , Sistemas de Liberação de Medicamentos , Polietilenoglicóis/química , Apoptose , Portadores de Fármacos/química , Doxorrubicina/farmacologia , Neoplasias/tratamento farmacológico
13.
Theranostics ; 14(5): 1939-1955, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505601

RESUMO

Rationale: Cancer continues to be a significant public health issue. Traditional treatments such as surgery, radiotherapy, and chemotherapy often fall short because of intrinsic issues such as lack of specificity and poor drug delivery, leading to insufficient drug concentration at the tumor site and/or potential side effects. Consequently, improving the delivery of conventional chemotherapy drugs like doxorubicin (DOX) is crucial for their therapeutic efficacy. Successful cancer treatment is achieved when regulated cell death (RCD) of cancer cells, which includes apoptotic and non-apoptotic processes such as ferroptosis, is fundamental to successful cancer treatment. The developing field of nanozymes holds considerable promise for innovative cancer treatment approaches. Methods: A dual-metallic nanozyme system encapsulated with DOX was created, derived from metal-organic frameworks (MOFs), designed to combat tumors by depleting glutathione (GSH) and concurrently liberating DOX. The initial phase of the study examined the GSH oxidase-mimicking function of the dimetallic nanozyme (ZIF-8/SrSe) through enzyme kinetic assays and Density Functional Theory (DFT) simulations. Following this, we probed the ability of ZIF-8/SrSe@DOX to release DOX in response to the tumor microenvironment in vitro, alongside examining its anticancer capabilities and mechanisms prompting apoptosis or ferroptosis in cancer cells. Moreover, we established tumor-bearing animal models to corroborate the anti-tumor effectiveness of our nanozyme complex and to identify the involved apoptotic and ferroptotic pathways implicated. Results: Enzyme kinetic analyses demonstrated that the ZIF-8/SrSe nanozyme exhibits substantial GSH oxidase-like activity, effectively oxidizing reduced GSH to glutathione disulfide (GSSG), while also inhibiting glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). This inhibition led to an imbalance in iron homeostasis, pronounced caspase activation, and subsequent induction of apoptosis and ferroptosis in tumor cells. Additionally, the ZIF-8/SrSe@DOX nanoparticles efficiently delivered DOX, causing DNA damage and further promoting apoptotic and ferroptotic pathways. Conclusions: This research outlines the design of a novel platform that combines chemotherapeutic agents with a Fenton reaction catalyst, offering a promising strategy for cancer therapy that leverages the synergistic effects of apoptosis and ferroptosis.


Assuntos
Ferroptose , Neoplasias , Morte Celular Regulada , Animais , Apoptose , Sistemas de Liberação de Medicamentos , Glutationa , Dissulfeto de Glutationa , Doxorrubicina/farmacologia , Oxirredutases , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Microambiente Tumoral
14.
J Mater Chem B ; 12(12): 3022-3030, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38426244

RESUMO

Lipid droplets (LDs) are cytoplasmic lipid-rich organelles with important roles in lipid storage and metabolism, cell signaling and membrane biosynthesis. Additionally, multiple diseases, such as obesity, fatty liver, cardiovascular diseases and cancer, are related to the metabolic disorders of LDs. In various cancer cells, LD accumulation is associated with resistance to cell death, reduced effectiveness of chemotherapeutic drugs, and increased proliferation and aggressiveness. In this work, we present a new viscosity-sensitive, green-emitting BODIPY probe capable of distinguishing between ordered and disordered lipid phases and selectively internalising into LDs of live cells. Through the use of fluorescence lifetime imaging microscopy (FLIM), we demonstrate that LDs in live cancer (A549) and non-cancer (HEK 293T) cells have vastly different microviscosities. Additionally, we quantify the microviscosity changes in LDs under the influence of DNA-damaging chemotherapy drugs doxorubicin and etoposide. Finally, we show that doxorubicin and etoposide have different effects on the microviscosities of LDs in chemotherapy-resistant A549 cancer cells.


Assuntos
Compostos de Boro , Gotículas Lipídicas , Neoplasias , Gotículas Lipídicas/metabolismo , Corantes Fluorescentes/farmacologia , Corantes Fluorescentes/metabolismo , Etoposídeo/metabolismo , Lipídeos , Doxorrubicina/farmacologia , Doxorrubicina/metabolismo , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
15.
J Gene Med ; 26(3): e3681, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38484722

RESUMO

Doxorubicin is a commonly used anti-cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance-associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC-CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell-derived cardiomyocytes (hiPSC-CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC-CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC-CM, with functional transporter activity leading to protection against doxorubicin-induced toxicity.


Assuntos
Cardiotoxicidade , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Miócitos Cardíacos , Humanos , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Células HEK293 , Doxorrubicina/farmacologia
16.
Carbohydr Polym ; 332: 121897, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38431408

RESUMO

Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA: 9.06 %). After hyaluronic acid (HA)-mediated endocytosis, the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles. Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc.; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer.


Assuntos
Micelas , Neoplasias , Humanos , Animais , Camundongos , 60576 , Ácido Hialurônico/farmacologia , Dextranos/metabolismo , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Resistencia a Medicamentos Antineoplásicos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistência a Múltiplos Medicamentos , Polímeros/metabolismo , Células MCF-7 , Mitocôndrias , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico
17.
Carbohydr Polym ; 332: 121931, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38431421

RESUMO

Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive radioactive therapy remains tedious and unsafe with severe adverse reactions and secondary injury. Herein, a composite hydrogel with pH- and photothermal double-sensitive activity is developed via physical crosslinking. The composite hydrogel incorporated with tempo-oxidized cellulose nanofiber (TOCN), polyvinyl alcohol (PVA) and a polydopamine (PDA) coating for photothermal therapy (PTT) triggered in situ release of doxorubicin (DOX) drug was utilized to optimize postoperative strategies of malignant tumors inhibition. The incorporation of TOCN significantly affects the performance of composite hydrogels. The best-performing TOCN/PVA7 was selected for drug loading and polydopamine coating by rational design. In vitro studies have demonstrated that the composite hydrogel exhibited high NIR photothermal conversion efficiency, benign cytotoxicity to L929 cells, pH-dependent release profiles, and strong MCF-7 cell inhibitory effects. Then the TOCN/PVA7-PDA@DOX hydrogel is implanted into the tumor resection cavity for local in vivo chemo-photothermal synergistical therapy to ablate residue tumor tissues. Overall, this work suggests that such a chemo-photothermal hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer.


Assuntos
Neoplasias da Mama , Celulose Oxidada , Hipertermia Induzida , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Terapia Fototérmica , Hidrogéis/química , Fototerapia , Mastectomia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Concentração de Íons de Hidrogênio
18.
Sci Rep ; 14(1): 6764, 2024 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514636

RESUMO

EBV-infected lymphoma has a poor prognosis and various treatment strategies are being explored. Reports suggesting that B cell lymphoma can be induced by epigenetic regulation have piqued interest in studying mechanisms targeting epigenetic regulation. Here, we set out to identify an epigenetic regulator drug that acts synergistically with doxorubicin in EBV-positive lymphoma. We expressed the major EBV protein, LMP1, in B-cell lymphoma cell lines and used them to screen 100 epigenetic modifiers in combination with doxorubicin. The screening results identified TCP, which is an inhibitor of LSD1. Further analyses revealed that LMP1 increased the activity of LSD1 to enhance stemness ability under doxorubicin treatment, as evidenced by colony-forming and ALDEFLUOR activity assays. Quantseq 3' mRNA sequencing analysis of potential targets regulated by LSD1 in modulating stemness revealed that the LMP1-induced upregulation of CHAC2 was decreased when LSD1 was inhibited by TCP or downregulated by siRNA. We further observed that SOX2 expression was altered in response to CHAC2 expression, suggesting that stemness is regulated. Collectively, these findings suggest that LSD1 inhibitors could serve as promising therapeutic candidates for EBV-positive lymphoma, potentially reducing stemness activity when combined with conventional drugs to offer an effective treatment approach.


Assuntos
Linfoma de Células B , Linfoma , Humanos , Herpesvirus Humano 4/genética , Lisina/metabolismo , Epigênese Genética , Linfoma/genética , Linfoma de Células B/genética , Histona Desmetilases/metabolismo , Doxorrubicina/farmacologia , Linhagem Celular Tumoral
19.
J Colloid Interface Sci ; 663: 1064-1073, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38458046

RESUMO

Doxorubicin (DOX) is widely used in clinic as a broad-spectrum chemotherapy drug, which can enhance the efficacy of chemodynamic therapy (CDT) by interfering tumor-related metabolize to increase H2O2 content. However, DOX can induce serious cardiomyopathy (DIC) due to its oxidative stress in cardiomyocytes. Eliminating oxidative stress would create a significant opportunity for the clinical application of DOX combined with CDT. To address this issue, we introduced sodium ascorbate (AscNa), the main reason is that AscNa can be catalyzed to produce H2O2 by the abundant Fe3+ in the tumor site, thereby enhancing CDT. While the content of Fe3+ in heart tissue is relatively low, so the oxidation of AscNa had tumor specificity. Meanwhile, due to its inherent reducing properties, AscNa could also eliminate the oxidative stress generated by DOX, preventing cardiotoxicity. Due to the differences between myocardial tissue and tumor microenvironment, a novel nanomedicine was designed. MoS2 was employed as a carrier and CDT catalyst, loaded with DOX and AscNa, coating with homologous tumor cell membrane to construct an acid-responsive nanomedicine MoS2-DOX/AscNa@M (MDA@M). In tumor cells, AscNa enhances the synergistic therapy of DOX and MoS2. In cardiomyocytes, AscNa could effectively reduce the cardiomyopathy induced by DOX. Overall, this study enhanced the clinical potential of chemotherapy synergistic CDT.


Assuntos
Cardiomiopatias , Neoplasias , Humanos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Nanomedicina , Peróxido de Hidrogênio/metabolismo , Molibdênio/metabolismo , Doxorrubicina/farmacologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Ácido Ascórbico/farmacologia , Linhagem Celular Tumoral , Neoplasias/metabolismo , Microambiente Tumoral
20.
Int J Pharm ; 654: 123969, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38442795

RESUMO

The current study used the precipitation method to prepare pure calcium hydroxyapatite (HA) and cerium-substituted hydroxyapatite (Ce-HA) nanoparticles, where cerium ions were exchanged into the HA structure at different concentrations ranging from 3 to 7 wt%. X-ray powder diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), Fourier transform infrared (FTIR) spectroscopy, Brunauer-Emmett-Teller (BET) surface area measurements, and zeta potential were used to examine the structural characteristics of the nanoparticles. Additionally, the antibacterial and antifungal effects of the produced materials on Gram-positive, Gram-negative, and fungal bacterial species were studied. Nanoparticles with cerium doping showed effective antibacterial and antifungal properties. All samples were tested for bioactivity in simulated body fluid (SBF), and the formation of an apatite layer on their surfaces was highlighted using SEM in conjunction with energy-dispersive X-rays (EDX).Doxorubicin (DOX) release from Ce-HA nanoparticles and pure HA was tested in phosphate-buffered saline (PBS) for up to 28 days. Both nanoparticles were able to release the drug while still being semi-fully loaded. Similarly, the cytotoxic effect of all produced samples on the MG-63 cell line was evaluated, and all samples showed good cytocompatibility. The cytotoxic effect of doxorubicin-loaded nanoparticles showed promising anticancer activity against bone cancer cells, especially samples with high cerium content. The resulting nanoparticles show excellent promising ability for the delivery of doxorubicin to bone cancer with the capacity for bone regeneration.


Assuntos
Neoplasias Ósseas , Cério , Nanopartículas , Humanos , Durapatita/química , Antifúngicos , Nanopartículas/química , Regeneração Óssea , Doxorrubicina/farmacologia , Antibacterianos , Difração de Raios X , Espectroscopia de Infravermelho com Transformada de Fourier
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