State-of-the-art therapeutic strategies for targeting cancer stem cells in prostate cancer.

The development of new therapeutic strategies is on the increase for prostate cancer stem cells, owing to current standardized therapies for prostate cancer, including chemotherapy, androgen deprivation therapy (ADT), radiotherapy, and surgery, often failing because of tumor relapse ability. Ultimately, tumor relapse develops into advanced castration-resistant prostate cancer (CRPC), which becomes an irreversible and systemic disease. Hence, early identification of the intracellular components and molecular networks that promote prostate cancer is crucial for disease management and therapeutic intervention. One of the potential therapeutic methods for aggressive prostate cancer is to target prostate cancer stem cells (PCSCs), which appear to be a primary focal point of cancer metastasis and recurrence and are resistant to standardized therapies. PCSCs have also been documented to play a major role in regulating tumorigenesis, sphere formation, and the metastasis ability of prostate cancer with their stemness features. Therefore, the current review highlights the origin and identification of PCSCs and their role in anti-androgen resistance, as well as stemness-related signaling pathways. In addition, the review focuses on the current advanced therapeutic strategies for targeting PCSCs that are helping to prevent prostate cancer initiation and progression, such as microRNAs (miRNAs), nanotechnology, chemotherapy, immunotherapy, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing system, and photothermal ablation (PTA) therapy.

Piperine Attenuates Lithocholic Acid-Stimulated Interleukin-8 by Suppressing Src/EGFR and Reactive Oxygen Species in Human Colorectal Cancer Cells.

Piperine, a natural alkaloidal pungent product present in pepper plants, possesses the properties of anti-inflammatory and anti-metastasis. Lithocholic acid is a monohydroxy-5beta-cholanic acid with an alpha-hydroxy substituent at position 3; it is a secondary bile acid that plays a pivotal role in fat absorption, and has been discovered to mediate colorectal cancer (CRC) cell invasion and migration. However, the effect of piperine on angiogenesis has been poorly investigated. In the current study, we examined the role of piperine on LCA-stimulated angiogenesis by measuring interleukin-8 (IL-8) expression; moreover, we revealed the potential molecular mechanisms in CRC cells. Here, we showed that piperine inhibited LCA-stimulated endothelial EA.hy926 cell angiogenesis in a conditioned medium obtained from colorectal HCT-116 cells. Experiments with an IL-8 neutralizer showed that IL-8 present in the conditioned medium was the major angiogenic factor. Piperine inhibited LCA-stimulated ERK1/2 and AKT via the Src/EGFR-driven ROS signaling pathway in the colorectal cell line (HCT-116). Through mutagenesis and inhibitory studies, we revealed that ERK1/2 acted as an upstream signaling molecule in AP-1 activation, and AKT acted as an upstream signaling molecule in NF-κB activation, which in turn attenuated IL-8 expression. Taken together, we demonstrated that piperine blocked LCA-stimulated IL-8 expression by suppressing Src and EGFR in human CRC HCT-116 cells, thus remarkably attenuating endothelial EA.hy926 cell tube formation.

Nanomedicine-based cancer immunotherapy: recent trends and future perspectives.

The combination of cancer immunotherapy with efficient functionalized nanosystems has emerged as a beneficial treatment strategy and its use has increased rapidly. The roles of stimuli-responsive nanosystems and nanomedicine-based cancer immunotherapy, a subsidiary discipline in the field of immunology, are pivotal. The present era is witnessing rapid advancements in the use of nanomedicine as a platform for investigating novel therapeutic applications and modern intelligent healthcare management strategies. The development of cancer nanomedicine has posthaste ratified the outcomes of immunotherapy to the subsequent stage in the current era of medical research. This review focuses on key findings with respect to the effectiveness of nanomedicine-based cancer immunotherapies and their applications, which include i) immune checkpoint inhibitors and nanomedicine, ii) CRISPR-Cas nanoparticles (NPs) in cancer immunotherapy, iii) combination cancer immunotherapy with core-shell nanoparticles, iv) biomimetic NPs for cancer immunotherapy, and v) CAR-T cells and cancer nanoimmunotherapy. By evaluating the state-of-the-art tools and taking the challenges involved into consideration, various aspects of the proposed nano-enabled therapeutic approaches have been discussed in this review.

Suppression of Urokinase-Type Plasminogen Activator Receptor by Docosahexaenoic Acid Mediated by Heme Oxygenase-1 in 12-O-Tetradecanoylphorbol-13-Acetate-Induced Human Endothelial Cells.

Urokinase-type plasminogen activator receptor (uPAR) plays a crucial role in inflammation and tumor metastasis. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been shown to exhibit anti-inflammatory and anti-tumor properties. However, the mechanism by which DHA negatively regulates uPAR expression is not yet understood. The aim of this study was to investigate the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and potential role of heme oxygenase-1 (HO-1) in DHA-induced inhibition of uPAR in human endothelial ECV304 cells. Results showed that TPA induced uPAR expression in a time dependent manner, while DHA inhibited uPAR expression in a concentration-dependent manner. Moreover, treatment with DHA induced HO-1 expression in a time- and concentration-dependent manner. In addition, DHA-induced inhibition of uPAR expression and cell invasion in TPA-stimulated cells was reversed by si-HO-1 RNA. Induction of HO-1 by ferric protoporphyrin IX (FePP) inhibited TPA-induced uPAR expression, and this effect was abolished by treatment with the HO-1 inhibitor tin protoporphyrin IX (SnPP). Additionally, carbon monoxide, an HO-1 product, attenuated TPA-induced uPAR expression and cell invasion. Collectively, these data suggest a novel role of DHA-induced HO-1 in reducing uPAR expression and cell invasion in human endothelial ECV304 cells.

Nootkatone, a Dietary Fragrant Bioactive Compound, Attenuates Dyslipidemia and Intramyocardial Lipid Accumulation and Favorably Alters Lipid Metabolism in a Rat Model of Myocardial Injury: An In Vivo and In Vitro Study.

In the present study, we assessed whether nootkatone (NKT), a sesquiterpene in edible plants, can provide protection against dyslipidemia, intramyocardial lipid accumulation, and altered lipid metabolism in a rat model of myocardial infarction (MI) induced by subcutaneous injections of isoproterenol (ISO, 85 mg/kg) on days 9 and 10. The rats were pre- and co-treated with NKT (10 mg/kg, p.o.) administered daily for 11 days. A significant reduction in the activities of myocardial creatine kinase and lactate dehydrogenase, as well as non-enzymatic antioxidants, and alterations in lipids and lipoproteins, along with a rise in plasma lipid peroxidation and intramyocardial lipid accumulation, were observed in ISO-treated rats. ISO administration induced alterations in the activities of enzymes/expressions that played a significant role in altering lipid metabolism. However, NKT treatment favorably modulated all biochemical and molecular parameters altered by ISO and showed protective effects against oxidative stress, dyslipidemia, and altered lipid metabolism, attributed to its free-radical-scavenging and antihyperlipidemic activities in rats with ISO-induced MI. Additionally, NKT decreased the accumulation of lipids in the myocardium as evidenced from Oil red O staining. Furthermore, the in vitro observations demonstrate the potent antioxidant property of NKT. The present study findings are suggestive of the protective effects of NKT on dyslipidemia and the underlying mechanisms. Based on our findings, it can be suggested that NKT or plants rich in NKT can be promising for use as a phytopharmaceutical or nutraceutical in protecting the heart and correcting lipid abnormalities and dyslipidemia, which are risk factors for ischemic heart diseases.

A modern era of personalized medicine in the diagnosis, prognosis, and treatment of prostate cancer.

The present era is witnessing rapid advancements in the field of medical informatics and modern healthcare management. The role of translational bioinformatics (TBI), an infant discipline in the field of medical informatics, is pivotal in this revolution. The development of high-throughput technologies [e.g., microarrays, next-generation sequencing (NGS)] has propelled TBI to the next stage in this modern era of medical informatics. In this review, we assess the promising translational outcomes of microarray- and NGS-based discovery of genes, proteins, micro RNAs, and other active biological compounds aiding in the diagnosis, prognosis, and therapy of prostate cancer (PCa) to improve treatment strategies at the localized and/or metastatic stages in patients. Several promising candidate biomarkers in circulating blood (miR-25-3p and miR-18b-5p), urine (miR-95, miR-21, miR-19a, and miR-19b), and prostatic secretions (miR-203) have been identified. AURKA and MYCN, novel candidate biomarkers, were found to be specifically expressed in neuroendocrine PCa. The use of BTNL2 gene mutations and inflammasomes as biomarkers in immune function-mediated, inherited PCa has also been elucidated based on NGS data. Although TBI discoveries can benefit clinical performance metrics, the translational potential and the in vivo performance of TBI outcomes need to be verified. In conclusion, TBI aids in the effective clinical management of PCa; furthermore, the fate of personalized/precision medicine mostly relies on the enhanced diagnostic, prognostic, and therapeutic potential of TBI.

Correction to: Evaluation of Wound Healing Potential of ß-Chitin Hydrogel/Nano Zinc Oxide Composite Bandage.

In the original manuscript, the platelet activation images of the sample treated groups, Fig. 3c were provided incorrectly.

Bacterial Resistance and Prostate Cancer Susceptibility Toward Metal-Ion-doped DNA Complexes.

DNA nanotechnology has laid a platform to construct a variety of custom-shaped nanoscale objects for functionalization of specific target materials to achieve programmability and molecular recognition. Herein, we prepared DNA nanostructures [namely, synthetic DNA rings (RDNA) and DNA duplexes extracted from salmon (SDNA)] containing metal ions (M2+) such as Cu2+, Ni2+, and Zn2+ as payloads for delivery to exterminate highly pathologic hospital bacterial strains (e.g., Escherichia coli and Bacillus subtilis) and prostate cancer cells (i.e., PC3, LNCaP, TRAMP-C1, 22Rv1, and DU145). Morphologies of these M2+-doped RDNA were visualized using atomic force microscopy. Interactions between M2+ and DNA were studied using UV-vis and Fourier transform infrared spectroscopy. Quantitative composition and chemical changes in DNA without or with M2+ were obtained using X-ray photoelectron spectroscopy. In addition, M2+-doped DNA complexes were subjected to antibacterial activity studies. They showed no bacteriostatic or bactericidal effects on bacterial strains used. Finally, in vitro cellular toxicity study was conducted to evaluate the effect of pristine DNA and M2+-doped DNA complexes on prostate cancer cells. Cytotoxicities conferred by M2+-doped DNA complexes for most cell lines were significantly higher than those of M2+ without DNA. Cellular uptake of these complexes was confirmed by fluorescence microscopy using PhenGreen FL indicator. On the basis of our observations, DNA nanostructures can be used as safe and efficient nanocarriers for delivery of therapeutics. They have enhanced therapeutic window than bare metals.

Metallo-Curcumin-Conjugated DNA Complexes Induces Preferential Prostate Cancer Cells Cytotoxicity and Pause Growth of Bacterial Cells.

DNA nanotechnology can be used to create intricate DNA structures due to the ability to direct the molecular assembly of nanostructures through a bottom-up approach. Here, we propose nanocarriers composed of both synthetic and natural DNA for drug delivery. The topological, optical characteristics, and interaction studies of Cu2+/Ni2+/Zn2+-curcumin-conjugated DNA complexes were studied using atomic force microscopy (AFM), UV-vis spectroscopy, Fourier transform infrared and mass spectroscopy. The maximum release of metallo-curcumin conjugates from the DNA complexes, triggered by switching the pH, was found in an acidic medium. The bacterial growth curves of E. coli and B. subtilis displayed a prolonged lag phase when tested with the metallo-curcumin-conjugated DNA complexes. We also tested the in vitro cytotoxicity of the metallo-curcumin-conjugated DNA complexes to prostate cancer cells using an MTS assay, which indicated potent growth inhibition of the cells. Finally, we studied the cellular uptake of the complexes, revealing that DNA complexes with Cu2+/Ni2+-curcumin exhibited brighter fluorescence than those with Zn2+-curcumin.

Prostate Cancer Cell-Specific Cytotoxicity of Sub-Micron Potassium Niobate Powder.

Oxide nanoparticles have numerous potential applications in medicine such as carriers for therapeutic drugs, contrast agents for bio-imaging and targeting agents for tumors. Oxide nanoparticles may also have an inherent cytotoxicity towards cancer cells, as recently found for cerium oxide. KNbO3 nanoparticles have a combination of low toxicity and nonlinear optical properties which make them attractive for use as a bio-imaging material. However, little is known yet about the cytotoxicity of KNbO3 particles towards cancerous cells. In the present work, the cytotoxicity of KNbO3 particles to normal and prostate cancer cell lines is studied. The mixed oxide method is used to prepare KNbO3 powder. Using dynamic light scattering the mean particle diameter of the KNbO3 powder is found to be ∼500 nm. X-ray diffraction, Fourier transform infra-red spectroscopy and Raman scattering spectroscopy are used to examine the structure of the KNbO3 powder. Powder morphology is examined using scanning electron microscopy. MTT assays of EA.hy926, PC-3 and DU-145 cell lines are carried out to study cell-specific cytotoxicity. KNbO3 sub-micron particles are found to have low toxicity to PC-3 cells, moderate toxicity to EA.hy926 cells and high toxicity to DU-145 cells. A new avenue towards the treatment of prostate cancer may be opened by the cell-specific cytotoxicity of KNbO3.

Computational Modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer.

The human HOXB13 gene encodes a 284 amino acid transcription factor belonging to the homeobox gene family containing a homeobox and a HoxA13 N-terminal domain. It is highly linked to hereditary prostate cancer, the majority of which is manifested as a result of a Single Nucleotide Polymorphism (SNP). In silico analysis of 95 missense SNP's corresponding to the non-homeobox region of HOXB13 predicted 21 nsSNP's to be potentially deleterious. Among 123 UTR SNPs analysed by UTRScan, rs543028086, rs550968159, rs563065128 were found to affect the UNR_BS, GY-BOX and MBE UTR signals, respectively. Subsequent analysis by PolymiRTS revealed 23 UTR SNPs altering the miRNA binding site. The complete HOXB13_M26 protein structure was modelled using MODELLER v9.17. Computational analysis of the 21 nsSNP's mapped into the HOXB13_M26 protein revealed seven nsSNP's (rs761914407, rs8556, rs138213197, rs772962401, rs778843798, rs770620686 and rs587780165) seriously resulting in a damaging and deleterious effect on the protein. G84E, G135E, and A128V resulted in increased, while, R215C, C66R, Y80C and S122R resulted in decreased protein stability, ultimately predicted to result in the altered binding patterns of HOXB13. While the genotype-phenotype based effects of nsSNP's were assessed, the exact biological and biochemical mechanism driven by the above predicted SNPs still needs to be extensively evaluated by in vivo and GWAS studies.

In silico analysis of the deleterious nsSNPs (missense) in the homeobox domain of human HOXB13 gene responsible for hereditary prostate cancer.

The human HOXB13 gene encodes a transcription factor containing a DNA-binding homeobox domain and a HoxA13 N-terminal domain. SNP is considered to be the primary genetic cause for hereditary prostate cancer (PCa). The study of functional nsSNPs would give an insight into the exact cause underlying the onset of hereditary PCa and possible methodologies for the cure or early management of the disease. Several in silico tools were used to screen and map the deleterious nsSNPs to the protein structure for predicting the structure-function effects. Among the 23 homeobox nsSNPs, sift predicted 20, whereas PolyPhen, panther, and provean predicted 21 nsSNP's as deleterious. W63R, D244N, K239Q, P222R, K218R, and G216C were found to have higher energy values than the native 2CRA. The RMSD value showed increased deviation for T253P(2.53 Å), P222R(2.27 Å), G216C(2.15 Å), K218R(1.66 Å), and K239Q(1.62 Å). The I-Mutant showed increase in the stability of R258C, S254T, S250L, K239Q, and Q227E. Ramachandran plot showed mutants P222R, G216C, W263R, and K218R having drastically unfavorable pattern of amino acid residues. The presence of these mutations may result in the altered structure and function of the transcription factor; however, the exact mechanism and pathology of those predicted nsSNPs should further be validated by in vivo experiments and population-based studies.

Assessment of Poly (vinyl alcohol) Coated Flutamide Nanoparticulates and their Efficacy on Prostate Cancer Cells.

BACKGROUND: Flutamide (FLT) is a non steroidal antiandrogenic drug used to treat prostate cancer. Its poor aqueous solubility and toxicity are the major hindrance for oral drug delivery. The aims of this study are to introduce nanoformulation of flutamide to increase its aqueous solubility thereby improves the therapeutic efficacy of the chemodrug. METHODS: Poly (vinyl alcohol) (PVA) coated flutamide nanoparticles (PVA FLT NPs) were formulated by nanoprecipitation method and characterized by DLS, TEM, FTIR, Drug release profile and biological assays. RESULTS: The PVA FLT nanoparticles were about 300nm size and spherical in shape. The PVA coated flutamide nanoparticles were monodispersed and polycrystalline. The FTIR spectra confirmed the encapsulation of flutamide in PVA FLT NPs. The encapsulation efficiency and loading efficiency was found to be about 78% and 15% respectively. The in vitro drug release of nanoparticles was calculated and it showed a sustained release up to 120 hrs at pH 7.4. The in vitro cytotoxicity, colony forming ability and blood compatibility were also investigated. The in vitro cytotoxicity study indicated the dose dependent cytotoxicity of PVA FLT NPs. In vitro clonogenic assay revealed that the PVA FLT NPs treated PC3 cells had less colony forming ability than the untreated PC3 cells. In vitro hemolysis assay and blood aggregation studies confirmed the hemocompatibility of the prepared PVA FLT NPs. CONCLUSION: We reported PVA coated FLT NPs were prepared by nanoprecipitation were more aqueous soluble than FLT, which increased its therapeutic efficacy for prostate cancer cells.