Abstract Pancreatic cancer is a complex disease accounting for fibrotic tumors and an aggressive phenotype. Gemcitabine (GEM) is used as a standard therapy, which develops chemoresistance leading to poor patient outcome. We have recently developed a superparamagnetic iron oxide nanoparticle (SPION) formulation of curcumin (SP-CUR), which is a nontoxic, bioactive anti-inflammatory/anti-cancer agent for its enhanced delivery in tumors. In this study, we demonstrate that SP-CUR effectively delivers bioactive curcumin to pancreatic tumors, simultaneously enhances GEM uptake and its efficacy. Mechanistic revelations suggest that SP-CUR targets tumor microenvironment via suppression of sonic hedgehog (SHH) pathway and an oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cells interaction. Increased GEM uptake was observed due to upregulation of the human nucleoside transporter genes (DCK, hCNT) and blocking ribonucleotide reductase subunits (RRM1/RRM2). Additionally, co-treatment of SP-CUR and GEM targets cancer stem cells by regulating pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc and Oct-4), and restricting tumor sphere formation. In an orthotopic mouse model, an enhanced accumulation of SP-CUR was found in pancreas, which potentiated GEM to reduce tumor growth and metastasis. Analysis of tumor tissues suggest that the treatment inhibits tumor stroma (α-SMA, Desmin and Hyluronic Acid) and induces changes in cell stiffness, as measured via Atomic Force Microscopy. This was accompanied by alteration of key cellular proteins of SHH signaling such as SHH, Gli-1, Gli-2, Sufu, and NFĸB-65 as indicated by Immunoblotting and Immunohistochemistry. These results suggest that SP-CUR has a great potential for future clinical use in the management of pancreatic cancer.
#1Myrna Hurtado(University of North Texas Health Science Center)H-Index: 5
#2Umesh T. Sankpal(University of North Texas Health Science Center)H-Index: 9
Last. Riyaz Basha(University of North Texas Health Science Center)H-Index: 24
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Abstract Pancreatic cancer (PC) continues to be a fatal malignancy. With standard treatments having modest impact, alternative courses of actions are being investigated such as enhancing the efficacy of standard treatment through sensitization of PC cells to chemotherapy or radiation. This review emphasizes investigational agents that increase the responses to chemotherapy or radiation in PC models. Our group has extensively investigated on Curcumin (Cur), analogs (EF31, UBS109, and L49H37), nan...
The complex environment surrounding pancreatic tumors helps these deadly malignancies to fend off chemotherapy. A drug called gemcitabine is commonly used for pancreatic ductal adenocarcinoma (PDAC), but most tumors become resistant, and patients have only an 8% chance of surviving five years after diagnosis. Xianjun Yu at China's Fudan University in Shanghai and colleagues review how the stroma, the dense mesh of proteins and connective tissue surrounding PDAC tumors, helps promote resistance. ...
Last. Haiming Fan(MOE: Chinese Ministry of Education)H-Index: 32
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Large-scale synthesis of monodisperse ultrasmall metal ferrite nanoparticles as well as understanding the correlations between chemical composition and MR signal enhancement is critical for developing next-generation, ultrasensitive T1 magnetic resonance imaging (MRI) nanoprobes. Herein, taking ultrasmall MnFe2O4 nanoparticles (UMFNPs) as a model system, we report a general dynamic simultaneous thermal decomposition (DSTD) strategy for controllable synthesis of monodisperse ultrasmall metal ferr...
Last. Gang-Feng Wang(Xi'an Jiaotong University)H-Index: 30
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The atomic force microscopy (AFM) has been widely used to measure the mechanical properties of biological cells through indentations. In most of existing studies, the cell is supposed to be linear elastic within the small strain regime when analyzing the AFM indentation data. However, in experimental situations, the roles of large deformation and surface tension of cells should be taken into consideration. Here, we use the neo-Hookean model to describe the hyperelastic behavior of cells and inve...
Cancer stem cells (CSCs) are important in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Agents with the ability to suppress CSCs are likely to provide novel opportunities for combating tumor proliferation and metastasis. The present study aimed to evaluate the effects of bufalin on pancreatic CSCs in vivo and in vitro. Using a serum-free suspension culture, tumor spheres were enriched in a gemcitabine-resistant human pancrea...
Progression of cancer is often associated with interactions between cancer cells and extracellular matrix (ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan (HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown ...
Last. Subhash C. Chauhan(UTHSC: University of Tennessee Health Science Center)H-Index: 49
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The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine (GEM). Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene (ORM), has potent ant...
#1Sheema Khan(UTHSC: University of Tennessee Health Science Center)H-Index: 23
#2Neeraj Chauhan(UTHSC: University of Tennessee Health Science Center)H-Index: 24
Last. Subhash C. Chauhan(UTHSC: University of Tennessee Health Science Center)H-Index: 49
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Pancreatic cancer is the fourth most prevalent cancer with about an 85% mortality rate; thus, an utmost need exists to discover new therapeutic modalities that would enhance therapy outcomes of this disease with minimal or no side effects. Ormeloxifene (ORM), a synthetic molecule, has exhibited potent anti-cancer effects through inhibition of important oncogenic and proliferation signaling pathways. However, the anti-cancer efficacy of ORM can be further improved by developing its nanoformulatio...
#1Digambara Patra(AUB: American University of Beirut)H-Index: 30
#2Riham El Kurdi(AUB: American University of Beirut)H-Index: 9
This review expands for the first time the development of curcumin as reducing and stabilizing agent. Curcumin is widely used in food industries, cosmetic domain and the biomedical field. The combi...
#1Korosh Morshedi(KAUMS: Kashan University of Medical Sciences)H-Index: 2
#2Sarina Borran(Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 5
Last. Amirhossein Sahebkar(MUMS: Mashhad University of Medical Sciences)H-Index: 104
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Gastrointestinal (GI) cancers with a high global prevalence are a leading cause of morbidity and mortality. Accordingly, there is a great need to develop efficient therapeutic approaches. Curcumin, a naturally occurring agent, is a promising compound with documented safety and anticancer activities. Recent studies have demonstrated the activity of curcumin in the prevention and treatment of different cancers. According to systematic studies on curcumin use in various diseases, it can be particul...
Despite advanced therapeutic strategies, the mortality and morbidity of pancreatic cancer (PC) have been increasing. This is due to the anomalous proliferation activity of stromal cells, like cancer-associated fibroblasts (CAFs), in the tumor microenvironment (TME). These cells develop resistance in the tumor cells, blocking the drug from entering the target tumor site, ultimately resulting in tumor metastasis. Additionally, the current conventional adjuvant techniques, including chemo and radio...
Last. Jose Prados(UGR: University of Granada)H-Index: 26
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The development of drug resistance is one of the main causes of cancer treatment failure. This phenomenon occurs very frequently in different types of cancer, including colon and pancreatic cancers. However, the underlying molecular mechanisms are not fully understood. In recent years, nanomedicine has improved the delivery and efficacy of drugs, and has decreased their side effects. In addition, it has allowed to design drugs capable of avoiding certain resistance mechanisms of tumors. In this ...
#1Jiaqi Tian(WMU: Weifang Medical University)H-Index: 4
#2Junxia Li(WMU: Weifang Medical University)H-Index: 4
Last. Lin Zhang(SDU: Shandong University)H-Index: 14
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Abstract Exposure to silica nanoparticles (SiNPs) has been suggested to cause physical disorders, yet the effects of SiNPs on female reproduction have not been illustrated. This study was implemented to explore the reproductive toxicity of SiNPs on female and reveal its underlying mechanisms. Methodologically, the fluorescein isothiocyanate (FITC)-SiNPs were synthesized by coupling with FITC and then used to track the biodistribution of SiNPs in vitro and in vivo. In total, 30 mice were intratra...
Aim Given the fact that tumor-associated macrophage-derived extracellular vesicles (EVs) are attributable to tumor aggressiveness, this research intends to decode the mechanism of M2 macrophage-derived EVs in the differentiation and activities of pancreatic cancer (PaCa) stem cells via delivering microRNA (miR)-21-5p. Methods Polarized M2 macrophages were induced, from which EVs were collected and identified. miR-21-5p expression in M2 macrophage-derived EVs was tested. After cell sorting, CD24+...
Iron oxide nanoparticles (IONPs) have been widely used for photothermal therapy and drug delivery applications. Curcumin (Cur) is a known anticancer and chemo-preventive molecule. Herein, we improved a simple method for preparing green synthesized curcumin-coated iron oxide nanoparticles (Cur-IONPs) to be used as a nano-platform to facilitate the combined chemo-photothermal therapy regimen. The prepared nano-formulations were characterized using transmission electron microscopy (TEM) and dynamic...
Last. Daishun Ling(ZJU: Zhejiang University)H-Index: 35
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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide due to its aggressiveness and the challenge to early diagnosis and treatment. In recent decades, nanomaterials have received increasing attention for diagnosis and therapy of PDAC. However, these designs are mainly focused on the macroscopic tumor therapeutic effect, while the crucial nano-bio interactions in the heterogeneous microenvironment of PDAC remain poorly understood. As a result, the majority of potent na...
Last. P. M. Dongre(MU: University of Mumbai)H-Index: 11
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The protein-nanoparticle interface plays a crucial role in drug binding and stability, in turn enhancing efficacy in targeted drug delivery. In the present study, whey protein β-lactoglobulin (BLG) is conjugated with gold nanoparticles (AuNP) and its interaction with curcumin (CUR) and gemcitabine (GEM) has been explored. Further, AuNP-BLG conjugate interactions with anticancer drugs were characterized using dynamic light scattering (DLS), zeta potential, UV-visible, Raman spectroscopy, fluoresc...
#2Xiaoying Sun(Soochow University (Suzhou))H-Index: 1
Last. Jian Li(CSU: Central South University)H-Index: 14
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Background Non-Hodgkin's lymphoma (NHL) possesses great heterogeneity in cytogenetics, immunophenotype and clinical features, and chemotherapy currently serves as the main treatment modality. Although employing monoclonal antibody targeted drugs has significantly improved its overall efficacy, various patients continue to suffer from drug resistance or recurrence. Chinese medicine has long been used in the treatment of malignant tumors. Therefore, we constructed a low pH value sensitivity drug d...