scholarly journals Self-transfecting GMO-PMO and PMO-GMO chimeras enable gene silencing in vitro and in vivo zebrafish model and NANOG Inhibition Induce the Apoptosis in Breast and Prostate Cancer Cells

2021 ◽  
Author(s):  
Jayanta Kundu ◽  
Ujjal Das ◽  
Chandra Bose ◽  
Jhuma Bhadra ◽  
Surajit Sinha
Keyword(s):  
Gene Silencing ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Zebrafish Model ◽  
No Tail ◽  
Delivery Technique ◽  
Breast And Prostate Cancer ◽  
Morpholino Oligonucleotides

Phosphorodiamidate Morpholino Oligonucleotides (PMOs)-based antisense reagents cannot enter inside cells by itself without the help of any delivery technique which is the last hurdle for their clinical applications. To overcome this limitation, a self-transfecting GMO-PMO or PMO-GMO chimeras has been explored as a gene silencing reagent where GMO stands for guanidinium morpholino oligonucleotides which linked either at the OH- or NH-end of PMOs. GMO not only facilitates cellular internalization of such chimeras but also participates in Watson-Crick base pairing during gene silencing in ShhL2 cells when designed against mGli1 and compared with scrambled GMO-PMO where mutations were made only to the GMO part. GMO-PMO-mediated knockdown of no tail gene resulted no tail-dependent phenotypes in zebrafish and worked even after the delivery at 16-, 32- and 64-cell stages which were previously unachievable by regular PMO. Furthermore, GMO-PMO chimeras has shown the inhibition of NANOG, a key regulator of self-renewal and pluripotency of both embryonic and cancer stem cells. Its inhibition influences on the expression of other cancer related proteins and the respective phenotypes in breast cancer cells and increases the therapeutic potential of taxol. To the best of our knowledge, this is the first report on the self-transfecting antisense reagents since the discovery of guanidinium linked DNA (DNG) and most effective among the all cell-penetrating PMOs reported till date expected to solve the longstanding problem of PMO delivery. In principle, this technology could be useful for the inhibition of any target gene without using any delivery vehicle and should have applications in the fields of antisense therapy, diagnostic and nanotechnology area.

scholarly journals miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Shihua Wu ◽  
Feng Liu ◽  
Liming Xie ◽  
Yaling Peng ◽  
Xiaoyuan Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Clinical Stage ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Progression

Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.

scholarly journals Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar ◽  
Kumari Sunita Prajapati ◽  
Mohd Shuaib ◽  
Prem Prakash Kushwaha ◽  
Hardeep Singh Tuli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Xenograft Models ◽  
Inhibitory Potential ◽  
Pharmacological Potential

In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2–62 µM while in vivo efficacy was studied in the range of 20–500 mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-κB, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models.

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice

2016 ◽  
Vol 26 (4) ◽  
pp. 610-618 ◽  
Author(s):  
Ikuko Sawada ◽  
Kae Hashimoto ◽  
Kenjiro Sawada ◽  
Yasuto Kinose ◽  
Koji Nakamura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Therapeutic Potential ◽  
Ovarian Cancer Cell Lines ◽  
Iκb Kinase ◽  
Xenograft Mice

ObjectiveAberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560,N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo.MethodsNF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model.ResultsThe NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation.ConclusionsIMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the treatment of ovarian cancer.

scholarly journals SENP Proteases as Potential Targets for Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2059
Author(s):  
Paulina Tokarz ◽  
Katarzyna Woźniak
Keyword(s):  
Cancer Cells ◽  
Therapeutic Potential ◽  
Cysteine Proteases ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Small Molecular Weight ◽  
Aberrant Expression

SUMOylation is a reversible post-translational modification (PTM) involving a covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMO-specific proteases (SENPs) are cysteine proteases with isopeptidase activity facilitating the de-conjugation of SUMO proteins and thus participating in maintaining the balance between the pools of SUMOylated and unSUMOylated proteins and in SUMO recycling. Several studies have reported that SENPs’ aberrant expression is associated with the development and progression of cancer. In this review, we will discuss the role of SENPs in the pathogenesis of cancer, focusing on DNA repair and the cell cycle—cellular pathways malfunctioning in most cancer cells. The plausible role of SENPs in carcinogenesis resulted in the design and development of their inhibitors, including synthetic protein-based, peptide-based, and small molecular weight inhibitors, as well as naturally occurring compounds. Computational methods including virtual screening have been implemented to identify a number of lead structures in recent years. Some inhibitors suppressed the proliferation of prostate cancer cells in vitro and in vivo, confirming that SENPs are suitable targets for anti-cancer treatment. Further advances in the development of SENP-oriented inhibitors are anticipated toward SENP isoform-specific molecules with therapeutic potential.

scholarly journals The Synergism of Platinum-Gold Bimetallic Nanoconjugates Enhances 5-Fluorouracil Delivery In Vitro

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 439 ◽  
Author(s):  
Vareessh Maney ◽  
Moganavelli Singh
Keyword(s):  
Cancer Cells ◽  
Colloidal Stability ◽  
Bimetallic Nanoparticles ◽  
Therapeutic Potential ◽  
Release Kinetics ◽  
High Specificity ◽  
In Vitro Cytotoxicity ◽  
Oral Drug

Nanoparticle application has significantly impacted the field of medicine. The need to develop novel drugs with higher therapeutic potential has stimulated the development of innovative delivery strategies to mitigate the potent side effects associated with known chemotherapeutic drugs. This paper describes the synthesis of platinum-gold bimetallic nanoparticles (PtAuBNps), their functionalisation with chitosan, and entrapment of the anticancer drug 5-fluorouracil (5-FU). All PtAuBNps and their drug nanocomposites were physico-chemically characterised, displaying desirable properties with regards to shape, size (<120 nm) and colloidal stability. 5-FU binding and loading capacities in PtAuBNps were found to be 90.17% and 22.56%, respectively. In vitro cytotoxicity profiles determined using the MTT and SRB assays reflected up to 65% cell death in the MCF-7, HepG2 and Caco-2 cell lines. These nanocomposites exhibited excellent physiochemical attributes, high specificity towards cancer cells, with a pH-sensitive drug release in a simulated acidic tumour microenvironment through zero-order release kinetics. In addition, they possessed the potential to traverse the mucosal lining facilitating oral drug administration. Overall, 5-FU encapsulation improved the bioavailability of the drug in cancer cells, with the promise of enhancing its therapeutic effect, biocompatibility and safety. These positive results highlight PtAuBNps as promising in vitro delivery systems and merits future in vivo research.

scholarly journals Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2189
Author(s):  
Wan-Pei Su ◽  
Wan-Jen Wang ◽  
Jean-Yun Chang ◽  
Pei-Chuan Ho ◽  
Tsung-Yun Liu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Epitope Peptide ◽  
Protein Targets ◽  
Signaling Complex ◽  
Cancer Suppression ◽  
Anticancer Response

Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.

scholarly journals Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Chen ◽  
Xu Cao ◽  
Bolei Li ◽  
Zhangchen Zhao ◽  
Siqi Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Evasion ◽  
Warburg Effect ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Extracellular Acidification ◽  
Extracellular Medium ◽  
The Warburg Effect

Evasion of immunosurveillance is critical for cancer initiation and development. The expression of “don’t eat me” signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major “don’t eat me” signal, via a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in in vitro phagocytosis assays and in vivo tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.

scholarly journals Anti-Inflammatory Activity of Exopolysaccharides from Phormidium sp. ETS05, the Most Abundant Cyanobacterium of the Therapeutic Euganean Thermal Muds, Using the Zebrafish Model

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 582 ◽  
Author(s):  
Raffaella Margherita Zampieri ◽  
Alessandra Adessi ◽  
Fabrizio Caldara ◽  
Alessia Codato ◽  
Mattia Furlan ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Chronic Inflammatory Disease ◽  
Bioactive Molecules ◽  
In Vitro Tests ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Beneficial Effects ◽  
Anti Inflammatory

The Euganean Thermal District (Italy) represents the oldest and largest thermal center in Europe, and its therapeutic mud is considered a unique product whose beneficial effects have been documented since Ancient Roman times. Mud properties depend on the heat and electrolytes of the thermal water, as well as on the bioactive molecules produced by its biotic component, mainly represented by cyanobacteria. The investigation of the healing effects of compounds produced by the Euganean cyanobacteria represents an important goal for scientific validation of Euganean mud therapies and for the discovering of new health beneficial biomolecules. In this work, we evaluated the therapeutic potential of exopolysaccharides (EPS) produced by Phormidium sp. ETS05, the most abundant cyanobacterium of the Euganean mud. Specifically, Phormidium EPS resulted in exerting anti-inflammatory and pro-resolution activities in chemical and injury-induced zebrafish inflammation models as demonstrated using specific transgenic zebrafish lines and morphometric and expression analyses. Moreover, in vivo and in vitro tests showed no toxicity at all for the EPS concentrations tested. The results suggest that these EPS, with their combined anti-inflammatory and pro-resolution activities, could be one of the most important therapeutic molecules present in the Euganean mud and confirm the potential of these treatments for chronic inflammatory disease recovery.

scholarly journals Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1164 ◽  
Author(s):  
Kai Tang ◽  
Ji Liu ◽  
Pamela Russell ◽  
Judith Clements ◽  
Ming-Tat Ling
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Prostate Cancer Cells ◽  
Tumour Metastasis ◽  
Wide Range ◽  
Anti Cancer ◽  
Gamma Tocotrienol

Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, γ-T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of γ-T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel γ-T3 downstream target. In prostate cancer cells, γ-T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of γ-T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of γ-T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using γ-T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer.

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