Recent advances and applications of peptide-agent conjugates for targeting tumor cells.

BACKGROUND: Cancer, being a complex disease, presents a major challenge for the scientific and medical communities. Peptide therapeutics have played a significant role in different medical practices, including cancer treatment. METHOD: This review provides an overview of the current situation and potential development prospects of anticancer peptides (ACPs), with a particular focus on peptide vaccines and peptide-drug conjugates for cancer treatment. RESULTS: ACPs can be used directly as cytotoxic agents (molecularly targeted peptides) or can act as carriers (guiding missile) of chemotherapeutic agents and radionuclides by specifically targeting cancer cells. More than 60 natural and synthetic cationic peptides are approved in the USA and other major markets for the treatment of cancer and other diseases. Compared to traditional cancer treatments, peptides exhibit anticancer activity with high specificity and the ability to rapidly kill target cancer cells. ACP's target and kill cancer cells via different mechanisms, including membrane disruption, pore formation, induction of apoptosis, necrosis, autophagy, and regulation of the immune system. Modified peptides have been developed as carriers for drugs, vaccines, and peptide-drug conjugates, which have been evaluated in various phases of clinical trials for the treatment of different types of solid and leukemia cancer. CONCLUSIONS: This review highlights the potential of ACPs as a promising therapeutic option for cancer treatment, particularly through the use of peptide vaccines and peptide-drug conjugates. Despite the limitations of peptides, such as poor metabolic stability and low bioavailability, modified peptides show promise in addressing these challenges. Various mechanism of action of anticancer peptides. Modes of action against cancer cells including: inducing apoptosis by cytochrome c release, direct cell membrane lysis (necrosis), inhibiting angiogenesis, inducing autophagy-mediated cell death and immune cell regulation.

D-allose: Molecular Pathways and Therapeutic Capacity in Cancer.

BACKGROUND: Despite the implementation of various cancer therapies, adequate therapeutic efficacy has not been achieved. A growing number of studies have been dedicated to the discovery of new molecules to combat refractory cancer cells efficiently. Recently, the use of a rare type of sugar, D-allose, has attracted the attention of research communities. In combination with the first-line treatment of cancers, including different types of radiotherapies and chemotherapies, D-allose has been detected with favorable complementary effects. Understanding the mechanism of therapeutic target molecules will enable us to develop new strategies for cancer patients that do not currently respond to the present therapies. OBJECTIVE: We aimed to provide a review of the effects of D-allose in cancer treatment, its mechanisms of action, and gaps in this field that require more investigations. DISCUSSION: With rare exceptions, in many cancer types, including head and neck, lung, liver, bladder, blood, and breast, D-allose consistently has exhibited anticancer activity in vitro and/or in vivo. Most of the D-allose functions are mediated through thioredoxin-interacting protein molecules. D-allose exerts its effects via reactive oxygen species regulation, cell cycle arrest, metabolic reprogramming, autophagy, apoptosis induction, and sensitizing tumors to radiotherapy and chemotherapy. CONCLUSION: D-allose has shown great promise for combating tumor cells with no side effects, especially in combination with first-line drugs; however, its potential for cancer therapy has not been comprehensively investigated in vitro or in vivo.

Combinatorial effects of telmisartan and docetaxel on cell viability and metastatic gene expression in human prostate and breast cancer cells.

The epithelial-to-mesenchymal transition (EMT) is a unique process resulting in enhanced cell motility, invasiveness, and metastasis in cancer. The EMT is regulated by several transcription factors, including Snail and Slug, which exert crucial roles during cancer progression. We have studied the effects of Docetaxel as the first-line chemotherapy agent for prostate cancer, and Telmisartan as an anti-hypertensive drug on the expression level of Snail and Slug. In addition, the effects of Docetaxel, Telmisartan and their combination on cancer cell proliferation were investigated. The PC3, DU145, MDA-MB468, and HEK cell lines were used for this study. Quantitative RT-PCR analysis and MTT assay were used to study the expression of Snail and Slug level and cell proliferative assay, respectively. We found that a combination of Docetaxel + Telmisartan effectively inhibits the cell proliferation in cancerous cells in comparison with each drug alone (P<0.05). Furthermore, in these cell lines, Docetaxel, Telmisartan and their combination significantly diminished the expression level of Snail and Slug genes compared to control cells (P<0.001), however, in the HEK cell line, this effect was seen only in the combination group. Our data imply that Telmisartan and its combination with Docetaxel exert strong inhibitory effects on the expression level of Snail and Slug genes. Also, these drugs and their combination could inhibit cancer cell proliferation. In conclusion, the combination of Telmisartan and Docetaxel has the potential to suppress the metastasis of prostate and breast cancer cells.

Telmisartan anti-cancer activities mechanism through targeting N-cadherin by mimicking ADH-1 function.

This study aimed to investigate if Telmisartan as a novel N-cadherin antagonist, can overcome cell migration of cancer cells. We investigated the mechanism and influence of Docetaxel and Telmisartan (as an analogous to ADH-1, which is a well-known N-cadherin antagonist) on cancer cells. The effect of ADH-1 and Telmisartan on cell attachment in PC3, DU145, MDA-MB-468 cell lines using recombinant human N-cadherin was studied. Cell viability assay was performed to examine the anti-proliferative effects of Telmisartan, ADH-1 and Docetaxel. Migration was examined via wound healing assay, and apoptosis was determined by flow cytometry. The expression of AKT-1 as a downstream gene of N-cadherin signalling pathway was assayed by real-time PCR. Treatment of PC3, MDA-MB-468 and DU145 cells with Telmisartan (0.1 µM) and ADH-1 (40 µM) resulted in 50%, 58% and approximately 20% reduction in cell attachment to N-cadherin coated plate respectively. It shows reduction of cell attachment in PC3 and MDA-MB-468 cell lines appeared to be more sensitive than that of DU145 cells to the Telmisartan and ADH-1 treatments. Telmisartan (0.1 µM) and Docetaxel (0.01 nM) significantly reduced cell migration in PC3 and MDA-MB-468 cell lines compared with the control group. Using Real-time PCR, we found that Telmisartan, Docetaxel and ADH-1 had significant influence on the AKT-1 mRNA level. The results of the current study for the first time suggest that, Telmisartan, exerts anti-proliferation and anti-migration effects by targeting antagonistically N-cadherin. Also, these data suggest that Telmisartan as a less expensive alternative to ADH-1 could potentiate Docetaxel anticancer effects.

Preconditioning with secretome of neural crest-derived stem cells enhanced neurotrophic expression in mesenchymal stem cells.

During the last 20 years, stem cell therapy has been considered as an effective approach for regenerative medicine. Due to poor ability of stem cells to survive following transplantation, it has been proposed that beneficial effects of stem cells mainly depend on paracrine function. Therefore, the present study was designed to reinforce mesenchymal stem cells (MSCs) to express higher levels of trophic factors especially the ones with the neurotrophic properties. Here, bone marrow (BM)-MSCs and adipose-MSCs were treated with conditioned medium (CM) of dental pulp stem cells (DPSCs) or hair follicle stem cells (HFSCs) for up to three days. The relative expression of five key trophic factors that have critical effects on the central nervous system regeneration were evaluated using qRT-PCR technique. Furthermore, to assess the impacts of conditioned mediums on the fate of MSCs, expression of seven neuronal/glial markers were evaluated 3 days after the treatments. The obtained data revealed priming of BM-MSCs with HFSC-CM or DPSC-CM increases the BDNF expression over time. Such effect was also observed in adipose-MSCs following DPSC-CM treatment. Secretome preconditioning remarkably increased NGF expression in the adipose-MSCs. In addition, although priming of adipose-MSCs with HFSC-CM increased GDNF expression one day after the treatment, DPSC-CM enhanced GDNF mRNA in BM-MSCs at a later time point. It seemed priming of BM-MSCs with HFSC-CM, promoted differentiation into the glial lineage. Our findings showed that MSCs preconditioning with secretome of neural crest-derived stem cells could be a promising approach to enhance the neurotrophic potential of these stem cells.

Efficacy of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in spinal cord injury in rats: Stereological evidence.

Spinal cord injury (SCI) causes histological alterations which in turn affects functional activity. Studies have demonstrated that dental pulp-derived stem cells conditioned medium has beneficial effects on the nervous system. Besides, collagen hydrogel acts as a drug releasing system in SCI investigations. This research aimed to evaluate effects of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in SCI. After culturing of Stem cells from human exfoliated deciduous teeth (SHEDs), SHED-conditioned medium (SHED-CM) was harvested and concentrated. Collagen hydrogel containing SHED-CM was prepared. The rats were divided into five groups receiving laminectomy, compressive SCI with or without intraspinal injection of biomaterials (SHED-CM and collagen hydrogel with or without SHED-CM). After 6 weeks, histological parameters were estimated using stereological methods. The total volume of preserved white matter and gray matter (p < 0.05) as well as the total number of neurons and oligodendrocytes in the rats received SHED-CM loaded in collagen hydrogel were significantly higher, and also lesion volume and lesion length were significantly lower (p < 0.05) compared to those of the other injured groups. In conclusion, intraspinal administration of SHED-CM loaded in collagen hydrogel leads to neuroprotection, proposing a cell-free therapeutic approach in SCI.

Cartilage Tissue and Therapeutic Strategies for Cartilage Repair.

High incidence of articular cartilage defects is still a major challenge in orthopedic and trauma surgery worldwide. It also has great socioeconomic effects as it is the major cause of disability in industrialized countries. This highlights the essential need for new treatments. Knowledge about the factors that have been implicated in the pathogenesis of cartilage diseases, including changes in the composition and structure of cartilaginous extracellular matrix (ECM), molecular factors and environmental signaling pathways could help the development of innovative therapeutic strategies. It is consensuses that the success of any technology aiming to repair chondral defects will be dependent upon its ability to produce tissues that most closely replicate the mechanical and biochemical properties of native cartilage. Increasing the knowledge about cartilage tissue and its molecular biomarkers could help find new and useful therapeutic approaches in cartilage damage. This review tries to describe cartilage tissue biology in detail and discuss different available therapeutic modalities with their pros and cons. New cartilage regeneration strategies and therapies, focusing on cellbased therapy and tissue engineering, and their underlying molecular and cellular bases will be pointed out as well.

Decellularized liver transplant could be recellularized in rat partial hepatectomy model.

In situ recellularization of the liver decellularized scaffold is a potential therapeutic alternative for liver transplantation. We aimed to develop an in situ procedure for recellularization of the rat liver using sodium lauryl ether sulfate (SLES) compared with Triton X-100/SDS. Rat liver specimens were rinsed with PBS, decellularized with either Triton X-100/SDS or SLES, and finally rinsed by distilled water. The efficiency of decellularized liver scaffolds was evaluated by histological, confocal Raman microscopy, histochemical staining, and DNA quantification assessments. Finally, in vivo studies were done to assess the biocompatibility of the liver scaffold by serum biochemical parameters and the recellularization capacity by histological and immunohistochemistry staining. Findings confirmed the preservation of extracellular matrix (ECM) components such as reticular, collagen, glycosaminoglycans, and neutral carbohydrates in both Triton X-100/SDS- and SLES-treated livers. Hoechst, feulgen, Hematoxylin and eosin, and DNA quantification assessments confirmed complete genetic content removal. The serological parameters showed no adverse impact on the liver functions. Transplantation of SLES-treated cell-free decellularized liver showed extensive neovascularization along with migration of the fibrocytes and adipocytes and some immune cells. Also, immunohistochemical staining showed that the oval cells, stellate cells, cholangiocytes and hepatocytes invaded extensively into the graft. It is concluded that SLES can be considered as a promising alternative in the liver decellularization process, and the transplanted decellularized liver can appropriately be revascularized and regenerated.

Deep analysis of N-cadherin/ADH-1 interaction: a computational survey.

Due to the considerable role of N-cadherin in cancer metastasis, tumor growth, and progression, inhibition of this protein has been highly regarded in recent years. Although ADH-1 has been known as an appropriate inhibitor of N-cadherin in clinical trials, its chemical nature and binding mode with N-cadherin have not been precisely specified yet. Accordingly, in this study, quantum mechanics calculations were used to investigate the chemical nature of ADH-1. These calculations clarify the molecular properties of ADH-1 and determine its reactive sites. Based on the results, the oxygen atoms are suitable for electrophilic reactivity, while the hydrogen atoms that are connected to nitrogen atoms are the favorite sites for nucleophilic reactivity. The higher electronegativity of the oxygen atoms makes them the most reactive portions in this molecule. Molecular docking and molecular dynamics (MD) simulation have also been applied to specify the binding mode of ADH-1 with N-cadherin and determine the important residues of N-cadherin involving in the interaction with ADH-1. Moreover, the verified model by MD simulation has been studied to extract the free energy value and find driving forces. These calculations and molecular electrostatic potential map of ADH-1 indicated that hydrophobic and electrostatic interactions are almost equally involved in the implantation of ADH-1 in the N-cadherin binding site. The presented results not only enable a closer examination of N-cadherin in complex with ADH-1 molecule, but also are very beneficial in designing new inhibitors for N-cadherin and can help to save time and cost in this field.

Sensory and Motor Behavior Evidences Supporting the Usefulness of Conditioned Medium from Dental Pulp-Derived Stem Cells in Spinal Cord Injury in Rats.

STUDY DESIGN: Experimental animal study. PURPOSE: This study aimed to assess effects of conditioned medium (CM) of dental pulp-derived stem cells loaded in collagen hydrogel on functional recovery following spinal cord injury (SCI). OVERVIEW OF LITERATURE: SCI affects sensory and motor functions, and behavioral recovery is the most essential purpose of therapeutic intervention. Recent studies have reported that CM from dental pulp-derived stem cells has therapeutic benefits. In addition, collagen hydrogel acts as a drug delivery system in SCI experiments. METHODS: Stem cells from human exfoliated deciduous teeth (SHEDs) were cultured, and SHED-CM was harvested and concentrated. Collagen hydrogel containing SHED-CM was prepared. The rats were divided into five groups receiving laminectomy, compressive SCI with or without intraspinal injection of biomaterials (SHED-CM), and collagen hydrogel with or without SHED-CM. Basso, Beattie, and Bresnahan (BBB) scoring, inclined plane, cold allodynia, and beam walk tests were performed for 6 weeks to assess locomotor, motor, sensory, and sensory-motor performances, respectively. RESULTS: Scores of the rats receiving SHED-CM loaded in collagen hydrogel were significantly better than those of the other injured groups at 1-week post-injury for BBB, 2 weeks for inclined plane, 2 weeks for cold allodynia, and 4 weeks for beam walk tests (p <0.05). The differences remained significant throughout the study. CONCLUSIONS: Intraspinal administration of SHED-CM loaded in collagen hydrogel leads to improved functional recovery and proposes a cell-free therapeutic approach for SCI.

HIF-1α Overexpression Induces Angiogenesis in Mesenchymal Stem Cells.

Stem cell therapy continues to be an innovative and promising strategy for heart failure. Stem cell injection alone, however, is hampered by poor cell survival and differentiation. This study was aimed to explore the possibility of improving stem cell therapy through genetic modification of stem cells, in order for them to promote angiogenesis in an auto- and paracrine manner under hypoxic conditions. Hypoxia inducible factor-1α was overexpressed in bone marrow-derived mesenchymal stem cells (MSCs) by stable transduction using a lentiviral vector. Under hypoxic and normoxic conditions, the vascular endothelial growth factor (VEGF) concentration in the cells' supernatant was measured by an enzyme-linked immunosorbent assay. Migration was assayed by wound healing and c-Met expression by flow cytometry. Tube formation was evaluated on a Matrigel basement membrane. The concentration of VEGF was significantly increased in the supernatant of HIF-1α-overexpressing MSCs; this medium was significantly more effective in inducing endothelial cell migration compared to untransduced MSCs. Transduced cells showed increased levels of c-Met expression and were more efficient at tube formation. However, no indication of differentiation toward an endothelial phenotype was observed. This study indicated that genetic modification of MSCs by HIF-1α overexpression has the potential to improve components of the angiogenesis process under a hypoxic condition by paracrine and autocrine mechanisms.