RESUMO
Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.
Assuntos
Proliferação de Células , Ácido Hialurônico , Melanoma , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias Uveais , Verteporfina , Verteporfina/farmacologia , Verteporfina/uso terapêutico , Animais , Fotoquimioterapia/métodos , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/patologia , Camundongos , Melanoma/tratamento farmacológico , Melanoma/patologia , Humanos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Linhagem Celular Tumoral , Nanopartículas/química , Proliferação de Células/efeitos dos fármacos , Ácido Hialurônico/química , Receptores de Hialuronatos/metabolismo , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP , Camundongos Nus , Terapia de Alvo Molecular/métodos , Camundongos Endogâmicos BALB C , FemininoRESUMO
BACKGROUND: Scutellaria barbata D. Don (SB), commonly known as Ban Zhi Lian and firstly documented by Shigong Chen, is a dried whole plant that has been studied for its therapeutic effects on breast cancer, colon cancer, and prostate cancer. Among its various compounds, scutellarin (SCU) has been demonstrated with anti-tumor effects. PURPOSE: This study aimed to evaluate the effects of SB water extract (SBW) and scutellarin on breast cancer stem cells (BCSCs), and to investigate their potential therapeutic effects on breast tumors in mice. METHODS: BCSCs were enriched from human breast cancer cells (MDA-MB-231 and MDA-MB-361) and their characteristics were analyzed. The effects of varying concentrations of SBW and scutellarin on cell viability, proliferation, self-renewal, and migration abilities were studied, along with the underlying mechanisms. The in vivo anti-tumor effects of scutellarin were further evaluated in SCID/NOD mice. Firstly, mice were inoculated with naïve BCSCs and subjected to treatment with scutellarin or vehicle. Secondly, BCSCs were pre-treated with scutellarin or vehicle prior to inoculation into mice. RESULTS: The derived BCSCs expressed CD44, CD133 and ALDH1, but not CD24, indicating that BCSCs have been successfully induced from both MDA-MB-231 and MDA-MB-361 cells. Both SBW and scutellarin reduced the viability, proliferation, sphere and colony formation, and migration of BCSCs. In mice with tumors derived from naïve BCSCs, scutellarin significantly reduced tumor growth, expression of proliferative (Ki67) and stem cell markers (CD44), and lung metastasis. In addition, pre-treatment with scutellarin also slowed tumor growth. Western blot results suggested the involvement of Wnt/ß-catenin, NF-κB, and PTEN/Akt/mTOR signaling pathways underlying the inhibitory effects of scutellarin. CONCLUSION: Our study demonstrated for the first time that both SB water extract and scutellarin could reduce the proliferation and migration of BCSCs in vitro. Scutellarin was shown to possess novel inhibitory activities in BCSCs progression. These findings suggest that Scutellaria barbata water extract, in particular, scutellarin, may have potential to be further developed as an adjuvant therapy for reducing breast cancer recurrence.
Assuntos
Apigenina , Neoplasias da Mama , Proliferação de Células , Glucuronatos , Camundongos Endogâmicos NOD , Células-Tronco Neoplásicas , Scutellaria , Animais , Apigenina/farmacologia , Scutellaria/química , Glucuronatos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos SCID , Antineoplásicos Fitogênicos/farmacologia , Camundongos , Extratos Vegetais/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Receptores de Hialuronatos/metabolismoRESUMO
CD44+ cancer stem cells (CSCs) are believed to account for drug resistance and tumour recurrence due to their potential to self-renew and differentiate into heterogeneous lineages. Therefore, efficient treatment strategies targeting and eliminating these CSCs are required. The flavonolignan, Silibinin, has gained immense attention in targeting CD44+ CSCs as it alters functional properties like cell cycle arrest, apoptosis, inhibition of invasion and metastasis and also inhibits a range of molecular pathways. However, its limited bioavailability is a major hurdle in asserting Silibinin as a translational therapeutic agent. Combinatorial therapy of Silibinin with conventional chemotherapeutic drugs is an alternative approach in targeting CD44+ CSCs as it increases the efficacy and reduces the cytotoxicity of chemotherapeutic drugs, thus preventing drug resistance. Certain Silibinin-conjugated nano-formulations have also been successfully developed, through which there is improved absorptivity/bioavailability of Silibinin and a decrease in the concentration of therapeutic drugs leading to reduced cytotoxicity. In this review, we summarise the effectiveness of the synergistic therapeutic approach for Silibinin in targeting the molecular mechanisms of CD44+ CSCs and emphasise the potential role of Silibinin as a novel therapeutic agent.
Assuntos
Neoplasias , Humanos , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/uso terapêutico , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas , Silibina/farmacologiaRESUMO
Aims: Achieving an effective biocompatible system for siRNAs delivery to the tumor site remains a significant challenge. Materials & methods: Selenium nanoparticles (SeNPs) modified by chitosan (CS) and hyaluronic acid (HA) were fabricated for PLK1 siRNAs (siPLK1) delivery to the bladder cancer cells. The HA-CS-SeNP@siPLK1 efficacy was evaluated using in vitro and in vivo models. Results: HA-CS-SeNP@siPLK1 was selectively internalized into T24 cells through clathrin-mediated endocytosis. Treatment with HA-CS-SeNP@siPLK1 successfully silenced the PLK1 gene, inhibited cell proliferation and induced cell cycle arrest in vitro. HA-CS-SeNP@siPLK1 could also inhibit tumor growth in vivo without causing systemic toxicity. Conclusion: Our results suggest that HA-CS-SeNPs may provide a good vehicle for delivering siPLK1 to the bladder tumor site.
siRNAs are small biomolecules shown as novel insights in cancer gene therapy because of their capability to silence target genes. However, achieving an effective biocompatible system for siRNA delivery to the tumor site remains a significant challenge. This work aimed to develop a nanoparticle-based delivery system consisting of selenium nanoparticles modified by chitosan and hyaluronic acid to sustain the release of siRNAs to bladder cancer cells. The results of this study demonstrated that this nanosystem successfully silenced the PLK1 gene and reduced the proliferation in vitro and in vivo. These findings suggest that hyaluronic acid-chitosan-selenium nanoparticles may open a new insight for targeted gene therapy for bladder cancer.
Assuntos
Quitosana , Nanopartículas , Selênio , Neoplasias da Bexiga Urinária , Humanos , RNA Interferente Pequeno/genética , Ácido Hialurônico , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismoRESUMO
PURPOSE: To investigate the expression and clinical significance of CD44 and CD33 in benign lymphoadenosis of oral mucosa(BLOM). METHODS: From January 2017 to March 2020, seventy-seven BLOM wax blocks from the Department of Pathology of Qingdao Traditional Chinese Medicine Hospital were selected as the experimental group, and 63 cases of normal oral mucosal tissue wax blocks during the same period were selected as the control group. Immunohistochemical method was used to detect the positive expression of CD44 and CD33 in the two groups.Spearman correlation analysis was used to analyze the correlation between the positive expression of CD33 and the positive expression of CD44 in the diseased tissues of BLOM patients.The general information about patients were collected.The relationship between the expression of CD33 and CD44 in the diseased tissues of BLOM patients and the clinicopathological characteristics of BLOM patients were analyzed. SPSS 21.0 software package was used for statistical analysis of the data. RESULTS: The positive expression rates of CD33 in the control group and the experimental group were 95.24% and 63.64%, respectively, and the difference was statistically significant(Pï¼0.05). The positive expression rates of CD44 in the control group and the experimental group were 93.65% and 67.53%, respectively, and the difference was statistically significant(Pï¼0.05). The results of Spearman correlation analysis showed that the positive expression of CD33 in the diseased tissues of BLOM patients was positively correlated with the positive expression of CD44 (r=0.834, P=0.002). The expression of CD33 and CD44 in the diseased tissues of patients with BLOM were related to clinical type, degree of inflammation, presence or absence of lymphoid follicles, and lymphocyte infiltration(Pï¼0.05), but not related to age, gender, course of disease, location, and epithelial surface keratinization(Pï¼0.05). CONCLUSIONS: The positive expression rate of CD33 and CD44 in the BLOM tissues decreased, which was closely related to the clinical type, degree of inflammation, presence or absence of lymphoid follicles, and lymphocyte infiltration.
Assuntos
Receptores de Hialuronatos , Doenças da Boca , Mucosa Bucal , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Relevância Clínica , Receptores de Hialuronatos/metabolismo , Mucosa Bucal/patologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Doenças da Boca/diagnóstico , Doenças da Boca/metabolismoRESUMO
Photothermal and photodynamic therapies (PTT/PDT) have been widely accepted as noninvasive therapeutic methods for cancer treatment. However, tumor hypoxia and insufficient delivery of photoactive compounds to cancer cells can reduce the efficacy of phototherapy. Herein, we first synthesized thiolated hyaluronic acid (THA) and then conjugated it with catalase (CAT) onto chlorin e6 (Ce6)-adsorbed small gold nanorods (Ce6@sAuNRs) with near-infrared (NIR)/visible light activated photothermal/photodynamic effects. The conjugation of THA and CAT on Ce6@sAuNRs resulted in a red-shift of the longitudinal LSPR absorption band of sAuNRs up to 1000 nm and maintained the excellent enzymatic activity of catalase. Modification of Ce6@sAuNRs with THA resulted in efficient internalization of the nanocomposite into MCF-7/ADR multidrug-resistant (MDR) breast cancer cells (CD44+), thereby significantly enhancing the intracellular accumulation of the photosensitizer Ce6. CAT endows Ce6@sAuNRs with self-supporting oxygen production, which enables them to efficiently generate singlet oxygen (1O2) under 660 nm laser irradiation and enhances the photodynamic effect against hypoxic breast cancer cells. The results highlight the prospect of this novel multi-functional nanoplatform integrating active biological macromolecules (THA and CAT) into photosensitizer/photothermal gold nanocomposites in overcoming the limitations of hypoxic MDR breast cancer cell treatment.
Assuntos
Neoplasias da Mama , Fotoquimioterapia , Porfirinas , Catalase , Ouro/farmacologia , Ácido Hialurônico/farmacologia , Oxigênio , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes , Porfirinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Humanos , Receptores de Hialuronatos , Nanotubos , Células MCF-7RESUMO
In the screening of novel natural products against cancer using an in vitro cancer cell model, we recently found that tanshinones from a traditional Chinese medicine, the rhizome of Salvia miltiorrhiza Bunge (Danshen), had potent effects on cell proliferation and migration. Especially for human osteosarcoma U-2 OS cells, tanshinones significantly enhanced the cell adherence, implying a possible role in cell adhesion and cell migration inhibition. In this work, therefore, we aimed to provide a new insight into the possible molecule mechanisms of dihydrotanshinone I, which had the strongest effects on cell adhesion among several candidate tanshinones. RNA-sequencing-based transcriptome analysis and several biochemical experiments indicated that there were comprehensive signals involved in dihydrotanshinone I-treated U-2 OS cells, such as cell cycle, DNA replication, thermogenesis, tight junction, oxidative phosphorylation, adherens junction, and focal adhesion. First, dihydrotanshinone I could potently inhibit cell proliferation and induce cell cycle arrest in the G0/G1 phase by downregulating the expression of CDK4, CDK2, cyclin D1, and cyclin E1 and upregulating the expression of p21. Second, it could significantly enhance cell adhesion on cell plates and inhibit cell migration, involving the hyaluronan CD44-mediated CXCL8-PI3K/AKT-FOXO1, IL6-STAT3-P53, and EMT signaling pathways. Thus, the increased expression of CD44 and lengthened protrusions around the cell yielded a significant increase in cell adhesion. In summary, these results suggest that dihydrotanshinone I might be an interesting molecular therapy for enhancing human osteosarcoma U-2 OS cell adhesion and inhibiting cell migration and proliferation.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Salvia miltiorrhiza , Adesão Celular , Movimento Celular , Quimiocinas , Furanos , Humanos , Receptores de Hialuronatos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Fenantrenos , Fosfatidilinositol 3-Quinases/metabolismo , Quinonas , Salvia miltiorrhiza/químicaRESUMO
Chemotherapy is the most common treatment strategy for cancer patients. Nevertheless, limited drug delivery to cancer cells, intolerable toxicity, and multiple drug resistance are constant challenges of chemotherapy. Novel targeted drug delivery strategies by using nanoparticles have attracted much attention due to reducing side effects and increasing drug efficacy. Therefore, the most important outcome of this study is to answer the question of whether active targeted HA-based drug nanocarriers have a significant effect on improving drug delivery to cancer cells.This study aimed to systematically review studies on the use of hyaluronic acid (HA)-based nanocarriers for chemotherapy drugs. The two databases MagIran and SID from Persian databases as well as international databases PubMed, WoS, Scopus, Science Direct, Embase, as well as Google Scholar were searched for human studies and cell lines and/or xenograft mice published without time limit until 2020. Keywords used to search included Nanoparticle, chemotherapy, HA, Hyaluronic acid, traditional medicine, natural medicine, chemotherapeutic drugs, natural compound, cancer treatment, and cancer. The quality of the studies was assessed by the STROBE checklist. Finally, studies consistent with inclusion criteria and with medium- to high-quality were included in the systematic review.According to the findings of studies, active targeted HA-based drug nanocarriers showed a significant effect on improving drug delivery to cancer cells. Also, the use of lipid nanoparticles with a suitable coating of HA have been introduced as biocompatible drug carriers with high potential for targeted drug delivery to the target tissue without affecting other tissues and reducing side effects. Enhanced drug delivery, increased therapeutic efficacy, increased cytotoxicity and significant inhibition of tumor growth, as well as high potential for targeted chemotherapy are also reported to be benefits of using HA-based nanocarriers for tumors with increased expression of CD44 receptor.
Assuntos
Antineoplásicos/uso terapêutico , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Lipossomos , Camundongos , Nanopartículas , Neoplasias/metabolismoRESUMO
Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to "see and treat" HNC. This method could also be applied to other types of cancer approachable with endoscopy.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Receptores de Hialuronatos/antagonistas & inibidores , Indóis/administração & dosagem , Compostos de Organossilício/administração & dosagem , Administração Intravenosa , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Endoscopia , Estudos de Viabilidade , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Imunoterapia , Indóis/química , Indóis/farmacologia , Camundongos , Imagem Óptica , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Fototerapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell's proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Receptores de Hialuronatos/genética , Hialuronan Sintases/genética , Ácido Hialurônico/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Bromelaínas/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/antagonistas & inibidores , Hialuronan Sintases/antagonistas & inibidores , Ácido Hialurônico/antagonistas & inibidores , Himecromona/uso terapêutico , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Piridonas/farmacologia , Piridonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
Herein, dual-bioresponsive of Rhein (RH) in promoting colonic mucous damage repair and controlling inflammatory reactions were combined by the dual-targeting (intestinal epithelial cells and macrophages) oral nano delivery strategy for effective therapy of ulcerative colitis (UC). Briefly, two carbohydrates, calcium pectinate (CP) and hyaluronic acid (HA) were used to modify lactoferrin (LF) nanoparticles (NPs) to encapsulate RH (CP/HA/RH-NPs). CP layer make CP/HA/RH-NPs more stable and protect against the destructive effects of the gastrointestinal environment and then release HA/RH-NPs to colon lesion site. Cellular uptake evaluation confirmed that NPs could specifically target and enhance the uptake rate via LF and HA ligands. in vivo experiments revealed that CP/HA/RH-NPs significantly alleviated inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway and accelerated colonic healing. Importantly, with the help of CP, this study was the first to attempt for LF as a targeting nanomaterial in UC treatment and offers a promising food-based nanodrug in anti-UC.
Assuntos
Antraquinonas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Ácido Hialurônico/química , Lactoferrina/química , Nanopartículas/química , Pectinas/química , Animais , Antraquinonas/química , Transporte Biológico , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Inibidores Enzimáticos/química , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/antagonistas & inibidores , Nanopartículas/uso terapêutico , Receptores de Superfície Celular/metabolismo , Proteínas de Junções Íntimas/metabolismo , Distribuição Tecidual , Receptor 4 Toll-Like/antagonistas & inibidoresRESUMO
Colorectal cancer (CRC) treatment is currently hindered by micrometastatic relapse that cannot be removed completely during surgery and is often chemotherapy resistant. Targeted theranostic nanoparticles (NPs) that can produce heat for ablation and enable tumor visualization via their fluorescence offer advantages for detection and treatment of disseminated small nodules. A major hurdle in clinical translation of nanoparticles is their interaction with the 3D tumor microenvironment. To address this problem tumor organoid technology was used to evaluate the ablative potential of CD44-targeted polymer nanoparticles using hyaluronic acid (HA) as the targeting agent and coating it onto hybrid donor acceptor polymer particles (HDAPPs) to form HA-HDAPPs. Additionally, nanoparticles composed from only the photothermal polymer, poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b']dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe), were also coated with HA, to form HA-BSe NPs, and evaluated in 3D. Monitoring of nanoparticle transport in 3D organoids revealed uniform diffusion of non-targeted HDAPPs in comparison to attenuated diffusion of HA-HDAPPs due to nanoparticle-matrix interactions. Computational diffusion profiles suggested that HA-HDAPPs transport may not be accounted for by diffusion alone, which is indicative of nanoparticle/cell matrix interactions. Photothermal activation revealed that only HA-BSe NPs were able to significantly reduce tumor cell viability in the organoids. Despite limited transport of the CD44-targeted theranostic nanoparticles, their targeted retention provides increased heat for enhanced photothermal ablation in 3D, which is beneficial for assessing nanoparticle therapies prior to in vivo testing.
Assuntos
Técnicas de Ablação/métodos , Terapia Fototérmica/métodos , Pontos Quânticos/uso terapêutico , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias Colorretais/terapia , Receptores de Hialuronatos , Ácido Hialurônico , Hipertermia Induzida , Indóis , Camundongos , Recidiva Local de Neoplasia/terapia , Organoides/metabolismo , Fotoquimioterapia , Polímeros , Pontos Quânticos/química , Nanomedicina Teranóstica/métodos , Tiadiazóis , Microambiente TumoralRESUMO
One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-ß (TGF-ß). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach.
Assuntos
Fármacos Anti-HIV/química , Compostos Heterocíclicos/química , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/antagonistas & inibidores , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Ligação Proteica , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/química , RNA Interferente Pequeno/metabolismoRESUMO
Photodynamic therapy (PDT) is frequently used to treat non-muscle invasive bladder cancer due its low toxicity and high selectivity. Since recurrence often occurs, alternative approaches and/or designs of combined therapies to improve PDT effectiveness are needed. This work aimed to evaluate the cytotoxicity of 4,6,4'-trimethylangelicin (TMA) photoactivated by blue light (BL) on human bladder cancer T24 cells and investigate the mechanisms underlying its biological effects. TMA/BL exerted antiproliferative activity through the induction of apoptosis without genotoxicity, as demonstrated by the expression levels of phospho-H2AX, an indicator of DNA double-stranded breaks. It also modulated the Wnt canonical signal pathway by increasing the phospho-ß-catenin and decreasing the nuclear levels of ß-catenin. The inhibition of this pathway was due to the modulation of the GSK3ß phosphorylation state (Tyr 216) that induces a proteasomal degradation of ß-catenin. Indeed, a partial recovery of nuclear ß-catenin expression and reduction of its phosphorylated form after treatment with LiCl were detected. As demonstrated by RT-PCR and cytofluorimetric analysis, TMA/BL also decreased the expression of CD44v6, a marker of cancer stem cells. Taken together, our data suggest that TMA photoactivated by BL may represent an interesting option for the photochemotherapy of noninvasive bladder carcinomas, since this treatment is able to inhibit key pathways for tumour growth and progression in the absence of genotoxic effects.
Assuntos
Carcinoma/tratamento farmacológico , Furocumarinas/química , Fotoquimioterapia/métodos , Fototerapia/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Apoptose , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Histonas/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Técnicas In Vitro , Luz , Fibras Ópticas , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Bexiga Urinária/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
CONTEXT: Breast cancer stem cells (bCSCs) are a small population of cancer-initiating cells within breast cancer, characterized as CD44+ CD24-/low. bCSCs develop apoptosis resistance by expressing survivin and suppressing caspase-9 and caspase-3 expression. Typhonium flagelliforme tuber extract (TFTe) can induce apoptosis in several types of cancer cells; however, the effects of TFTe to induce the bCSCs remain unclear. AIMS: This study aimed to investigate the effects of TFTe on apoptosis induction in bCSCs through the suppression of survivin and the exhibition of caspase-9 and caspase-3. SETTINGS AND DESIGN: This study employed a posttest only, control group design. SUBJECTS AND METHODS: To analyze the apoptotic index, TFTe, at concentrations of 25 (Tf1d), 50.89 (Tf2d), and 100 µg/mL (Tf3d) were used to treat bCSCs for 24 h, in a humidified incubator containing 5% CO2, at 37°C. The control group was exposed to dimethyl sulfoxide. Apoptosis was measured by propidium iodide and acridine orange double-staining, and the expression levels of survivin, caspase-9, and caspase-3 were assessed by immunocytochemistry. STATISTICAL ANALYSIS USED: Differences were analyzed by the independent Student's t-test, to compare two groups, and the Kruskal-Wallis test, to compare more than two groups. P < 0.05 was considered statistically significant. RESULTS: TFTe inhibited bCSC proliferation, with an IC50 value of 50.89 µg/mL, and significantly induced apoptosis in bCSCs (P < 0.001). TFTe also significantly decreased the expression levels of survivin in bCSCs (P < 0.001) and increased the expression levels of caspase-9 and caspase-3 (P < 0.001). CONCLUSIONS: TFTe can induce apoptosis in bCSCs by decreasing survivin expression levels and increasing the levels of caspase-9 and caspase-3.
Assuntos
Araceae/química , Neoplasias da Mama/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Survivina/antagonistas & inibidores , Apoptose/fisiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Survivina/metabolismoRESUMO
Despite the considerable advances in treatment method development, the mortality rate related to colon cancer still ranks the fifth in all tumor-related diseases. Recently, there has been growing evidences supporting the existence of colon cancer stem cells (CSCs) might be one of the main causes for initiation, progression and recurrence of colon cancer. Curcumin has been shown to possess anticancer activities. It has also been suggested that curcumin was effective against colon CSCs by coupling with CD44, a robust marker and functional important molecule for colorectal CSC. In the present study, we confirmed that curcumin can inhibit the proliferation, colony formation, migration and tumor sphere formation of colon cancer cells. Results from real-time PCR and western blotting had suggested that curcumin could down-regulate the expression of CD44. Moreover, results from flow cytometry had further revealed that curcumin could decrease the proportion of CD44+ colon cancer cells. After the expression of CD44 had been knocked down by using siRNA, the inhibition effects of curcumin against CD44+ colon cancer cells were observed to be reduced significantly. Moreover, it had been observed that the cellular uptake of curcumin was significantly higher in CD44+ colon cancer cells. Results from flow cytometry had shown that curcumin could induce apoptosis in CD44+ colon cancer cells. Altogether, our results suggested that curcumin might be an adjuvant drug for the treatment of colorectal cancer by targeting CD44.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Curcumina/uso terapêutico , Receptores de Hialuronatos/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Curcumina/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genéticaRESUMO
Purpose: Tofacitinib is a pan-Janus kinase (JAK) inhibitor that suppresses cytokine signaling and in turn, the cells that participate in inflammatory immunopathogenic processes. We examined the capacity of tofacitinib to inhibit the induction of experimental autoimmune uveitis (EAU) and related immune responses. Methods: EAU was induced in B10.A mice with immunization with bovine interphotoreceptor retinoid-binding protein (IRBP), emulsified in complete Freund's adjuvant (CFA), and a simultaneous injection of pertussis toxin. Tofacitinib, 25 mg/kg, was administered daily, and the vehicle was used for control. EAU development was assessed by histological analysis of the mouse eyes, and related immune responses were assessed by (i) the levels of interferon (IFN)-γ and interleukin (IL)-17, secreted by spleen cells cultured with IRBP; (ii) flow cytometric analysis of intracellular expression by spleen, or eye-infiltrating CD4 or CD8 cells of IFN-γ, IL-17, and their transcription factors, T-bet and RORγt. In addition, the inflammation-related cell markers CD44 and CD62L and Ki67, a proliferation marker, were tested. The proportions of T-regulatory cells expressing FoxP3 were determined by flow cytometric intracellular staining, while levels of antibody to IRBP were measured with enzyme-linked immunosorbent assay (ELISA). Results: Treatment with tofacitinib significantly suppressed the development of EAU and reduced the levels of secreted IFN-γ, but not of IL-17. Further, treatment with tofacitinib reduced in the spleen and eye-infiltrating cells the intracellular expression of IFN-γ and its transcription factor T-bet. In contrast, treatment with tofacitinib had essentially no effect on the intracellular expression of IL-17 and its transcription factor, RORγt. The selective effect of tofacitinib treatment was particularly evident in the CD8 population. Treatment with tofacitinib also increased the population of CD44, but reduced the populations of cells producing CD62L and Ki67. Treatment with tofacitinib had no effect on the proportion of FoxP3 producing regulatory cells and on the antibody production to IRBP. Conclusions: Treatment with tofacitinib inhibited the development of EAU, reduced the production of IFN-γ, but had essentially no effect on the production of IL-17.
Assuntos
Olho/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Uveíte/tratamento farmacológico , Uveíte/imunologia , Animais , Antígenos CD4/sangue , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/sangue , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Olho/efeitos dos fármacos , Olho/patologia , Proteínas do Olho/farmacologia , Fatores de Transcrição Forkhead/sangue , Receptores de Hialuronatos/sangue , Terapia de Imunossupressão , Interferon gama/sangue , Interleucina-17/sangue , Antígeno Ki-67/sangue , Selectina L/sangue , Camundongos , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Proteínas de Ligação ao Retinol/farmacologia , Células Th1/imunologia , Células Th17/imunologiaRESUMO
BACKGROUND: Since enhanced bone resorption due to osteoclast differentiation and activation cause skeletal diseases, there is a growing need in therapeutics for combating bone-resorbing osteoclasts. Botanical antioxidants are being increasingly investigated for their health-promoting effects on bone. Edible Cirsium setidens contains various polyphenols of linarin, pectolinarin, and apigenin with antioxidant and hepatoprotective effects. PURPOSE: This study aimed to determine whether linarin present in Cirsium setidens water extracts (CSE) and its aglycone acacetin inhibited osteoclastogenesis of RANKL-exposed RAW 264.7 murine macrophages for 5 days. METHODS: This study assessed the osteoprotective effects of CSE, linarin and acacetin on RANKL-induced differentiation and activation of osteoclasts by using MTT assay, TRAP staining, Western blot analysis, bone resorption assay actin ring staining, adhesion assay and immunocytochemical assay. This study explored the underlying mechanisms of their osteoprotection, and identified major components present in CSE by HPLC analysis. RESULTS: Linarin and pectolinarin were identified as major components of CSE. Nontoxic linarin and acacetin as well as CSE, but not pectolinarin attenuated the RANKL-induced macrophage differentiation into multinucleated osteoclasts, and curtailed osteoclastic bone resorption through reducing lacunar acidification and bone matrix degradation in the osteoclast-bone interface. Linarin and acacetin in CSE reduced the transmigration and focal contact of osteoclasts to bone matrix-mimicking RGD peptide. Such reduction was accomplished by inhibiting the induction of integrins, integrin-associated proteins of paxillin and gelsolin, cdc42 and CD44 involved in the formation of actin rings. The inhibition of integrin-mediated actin ring formation by linarin and acacetin entailed the disruption of TRAF6-c-Src-PI3K signaling of bone-resorbing osteoclasts. The functional inhibition of c-Src was involved in the loss of F-actin-enriched podosome core protein cortactin-mediated actin assembly due to linarin and acacetin. CONCLUSION: These observations demonstrate that CSE, linarin and acacetin were effective in retarding osteoclast function of focal adhesion to bone matrix and active bone resorption via inhibition of diffuse cloud-associated αvß3 integrin and core-linked CD44.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Flavonas/farmacologia , Adesões Focais/efeitos dos fármacos , Glicosídeos/farmacologia , Osteoclastos/efeitos dos fármacos , Actinas/metabolismo , Animais , Matriz Óssea/efeitos dos fármacos , Matriz Óssea/metabolismo , Reabsorção Óssea/metabolismo , Cirsium/química , Adesões Focais/metabolismo , Receptores de Hialuronatos/metabolismo , Integrina alfaVbeta3/metabolismo , Camundongos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Células RAW 264.7RESUMO
Nanomedicines such as liposomes have been widely exploited in the treatment of tumors, and are also involved in combination therapies to enhance anti-tumor efficacy and reduce side effects. However, few studies have systematically discussed the significance and optimized regimens for nanomedicine-based combination therapy. In this study, we used anti-inflammatory and anti-tumor liposomes for co-administration, and compared three regimens: intermittent, metronomic, or sequential administration (IA, MA, and SA). The anti-inflammatory liposome HA/TN-CCLP was constructed in our previous research, which co-loaded curcumin (CUR) and celecoxib (CXB), modified with TAT-NBD peptide (TN) and finally coated with hyaluronic acid (HA), thereby inhibiting NF-κB and STAT3 pathways in the treatment of metastatic breast cancer. Furthermore, doxorubicin liposomes with and without TN modification (namely TN-DOXLP and DOXLP) were constructed and administrated with HA/TN-CCLP. The anti-tumor and anti-metastasis efficacy of different regimens was investigated. Results showed that in vitro cytotoxicity of DOXLP and TN-DOXLP was significantly enhanced when combined with HA/TN-CCLP. In vivo experiments also revealed the superiority of three combination therapies in inhibiting tumor growth, prolonging the survival of tumor-bearing mice, inducing apoptosis, and reducing lung metastases. In particular, the combination therapy could reduce MDSCs (Gr-1+/CD11b+) and CSCs (CD44+/CD24+) infiltration, which are two important factors in tumor metastasis and recurrence. Among three regimens, sequential administration (SA) showed the best therapeutic outcome and was especially effective for the inhibition of CSCs. In general, the results demonstrated that combination therapy, particularly the sequential administration of anti-inflammatory and anti-tumor liposome, was superior to monotherapy in inhibiting the development and metastasis of inflammation-related tumors.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lipossomos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Celecoxib/farmacologia , Curcumina/farmacologia , Doxorrubicina/análogos & derivados , Feminino , Humanos , Receptores de Hialuronatos , Ácido Hialurônico/farmacologia , Camundongos , Nanomedicina , Metástase Neoplásica , PolietilenoglicóisRESUMO
Triptolide, an ingredient of Tripterygium wilfordii, has been demonstrated to possess many biological activities such as immunomodulatory, antitumor activity in experiment. The purpose of this study was to survey the toxicity of TPL-PEI-CyD on renal cells and its effects on breast carcinoma stem cells. The cytotoxicity of TPL-PEI-CyD and TPL on HK-2 was comparatively assessed by CCK-8. After incubation and culturing with TGF-ß1, the MCF-7 cells were assessed by flow cytometry for the proportion of CD44+> CD24- cells; then the CD44>+> CD24- cells were sorted by immunomagnetic beads as MCF-7 stem cells. To assess the effect of TPL-PEI-CyD on MCF-7 stem cells, Western Blot was used to detect the expression of Oct-4 and ALDHl in MCF-7 stem cells after being dosed with TPL- PEI-CyD. Results showed that, compared with TPL, the toxicity of TPL-PEI-CyD on HK-2 cells was significantly reduced (P<0.05). Breast carcinoma stem cells can be enriched by TGF-ß1 and isolated from MCF-7 cells by immunomagnetic sorting. TPL- PEI-CyD can even more significantly suppress the expression of Oct-4 and ALDHA1 in MCF-7 stem cells than TPL (P<0.05). In conclusion, after coupling TPL and PEI-CyD, TPL-PEI-CyD showed characteristics of effective suppression to breast carcinoma stem cell and decrease of cytotoxicity. It presented the unique effect of traditional Chinese medicine as an efficient and low toxic drug carrier complex for breast carcinoma treatment.