Homology modeling, virtual screening, molecular docking, and ADME approaches to identify a potent agent targeting NK2R protein.

Neurokinin/tachykinin receptors are classified as the G-protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues. NK2R is associated with a range of biological events, such as inflammation, smooth muscle contraction, intestinal motor functions, and asthma. Despite these diverse activities, no approved drugs targeting NK2R have been developed yet. Our study focuses on finding potential inhibitors for NK2R using virtual screening, molecular docking, and ADME (absorption, distribution, metabolism, and excretion) approaches. We used a homology modeling approach and AlphaFold DB to obtain the three-dimensional structure of mouse and human NK2R proteins, respectively. The homology model of NK2R was predicted using MODELLER v10.3 and further refined and validated using the 3Drefine tool and RAMPAGE server, respectively. Molecular docking was performed using a library of 910 structurally similar molecules to four NK1R antagonists: aprepitant, casopitant, fosaprepitant, and rolapitant. Molecular docking revealed six small molecules that displayed high Chemscore fitness scores, and binding energies with desirable ligand-NK2R interactions. The evaluation of the in silico ADME profile, solubility, and permeability of the ligand molecules has revealed that the small molecules are potentially nontoxic and have the chance of exhibiting biological activity after oral administration. Further experimental studies (in vitro and in vivo assays) are required to evaluate the effectiveness of these inhibitors as therapeutic targets.

Rigosertib is more potent than wortmannin and rapamycin against adult T-cell leukemia-lymphoma.

Human T lymphotropic virus type 1 (HTLV-1) infection can cause adult T-cell lymphoblastic leukemia (ATLL), an incurable, chemotherapy-resistant malignancy. In a quest for new therapeutic targets, our study sought to determine the levels of AKT, mTOR, and PI3K in ATLL MT-2 cells, HTLV-1 infected NIH/3T3 cells (Inf-3T3), and HTLV-1 infected patients (Carrier, HAM/TSP, and ATLL). Furthermore, the effects of rigosertib, wortmannin, and rapamycin on the PI3K/Akt/mTOR pathway to inhibit the proliferation of ATLL cells were examined. The results showed that mRNA expression of Akt/PI3K/mTOR was down-regulated in carrier, HAM/TSP, and ATLL patients, as well as MT-2, and Inf-3T3 cells, compared to the healthy individuals and untreated MT-2 and Inf-3T3 as controls. However, western blotting revealed an increase in the phosphorylated and activated forms of AKT and mTOR. Treating the cells with rapamycin, wortmannin, and rigosertib decreased the phosphorylated forms of Akt and mTOR and restored their mRNA expression levels. Using these inhibitors also significantly boosted the expression of the pro-apoptotic genes, Bax/Bcl-2 ratio as well as the expression of the tumor suppressor gene p53 in the MT-2 and Inf-3T3cells. Rigosertib was more potent than wortmannin and rapamycin in inducing sub-G1 and G2-M cell cycle arrest, as well as late apoptosis in the Inf-3T3 and MT-2 cells. It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV-1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K-Akt-mTOR phosphorylation by HTLV-1. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.

Thymol has anticancer effects in U-87 human malignant glioblastoma cells.

BACKGROUND: Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). METHODS AND RESULTS: Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration (IC50) of thymol in the U-87 cells was 230 µM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. CONCLUSIONS: Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.

PD-1 and PD-L1 inhibitors foster the progression of adult T-cell Leukemia/Lymphoma.

Immunotherapy through immune checkpoints blockade and its subsequent clinical application has revolutionized the treatment of a spectrum of solid tumors. Blockade of Programmed cell death protein-1 and its ligand has shown promising results in clinical studies. The clinical trials that enrolled patients with different hematopoietic malignancies including non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia (AML) showed that anti-PD-1 agents could have potential therapeutic effects in the patients. Adult T-cell leukemia/lymphoma (ATLL) is a non-Hodgkin T-cell Lymphoma that is developed in a minority of HTLV-1-infected individuals after a long latency period. The inhibition of PD-1 as a treatment option is currently being investigated in ATLL patients. In this review, we present a summary of the biology of the PD-1/PD-L1 pathway, the evidence in the literature to support anti-PD-1/PDL-1 application in the treatment of different lymphoid, myeloid, and virus-related hematological malignancies, and controversies related to PD-1/PD-L1 blocking in the management of ATLL patients.

Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer.

Colorectal cancer (CRC) is the third commonest cancer globally, with metastasis being the reason for cancer-associated mortality. Much is still unknown biochemically about CRC, and with current treatments that are not wholly effective over time, new therapeutics are urgently needed. Emerging evidence has shown the importance of non-coding RNAs such as lncRNAs and miRNAs functions in the development and progression of CRC. However, the exact underlying mechanism of these types of RNAs in CRC is still mostly unknown. PI3K/AKT/mTOR pathway contributes to many cellular processes, and dysregulation of this pathway frequently occurs in cancers. In this review, the authors have mostly focused on the significant non-coding RNAs regulators of the PI3K/AKT/mTOR pathway and their contribution to the development or inhibition of CRC and their potential as diagnostic or therapeutic targets in CRC treatment.

Neurokinin-1 Receptor (NK-1R) Antagonists: Potential Targets in the Treatment of Glioblastoma Multiforme.

The current standard of care in glioblastoma multiforme (GBM), as the most morbid brain tumor, is not adequate, despite substantial progress in cancer therapy. Among patients receiving current standard treatments, including surgery, irradiation, and chemotherapy, the overall survival (OS) period with GBM is less than one year. The high mortality frequency of GBM is due to its aggressive nature, including accelerated growth, deregulated apoptosis, and invasion into surrounding tissues. The understanding of the molecular pathogenesis of GBM is, therefore, crucial for identifying, designing, and repurposing potential agents in future therapeutic approaches. In recent decades, it has been apparent that several neurotransmitters, specifically substance P (SP), an undecapeptide in the family of neuropeptides tachykinins, are found in astrocytes. After binding to the neurokinin-1 receptor (NK-1R), the SP controls cancer cell growth, exerts antiapoptotic impacts, stimulates cell invasion/metastasis, and activates vascularization. Since SP/NK-1R signaling pathway is a growth driver in many cancers, this potential mechanism is proposed as an additional target for treating GBM. Following an evaluation of the function of both SP and its NK-1R inhibitors in neoplastic cells, we recommend a unique and promising approach for the treatment of patients with GBM.

Protective Role of Natural Products in Glioblastoma Multiforme: A Focus on Nitric Oxide Pathway.

In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.

Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors.

INTRODUCTION: Inhibition of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed. METHODS: A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. The parent molecule and derivatives were then docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in drug-likeness screening by Swiss-ADME or at the docking stage. RESULTS: The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to - 58.3 and -54.5 KJ/mol, respectively. CONCLUSION: In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using a fragment-based approach.

Modulation of Calcium Signaling in Glioblastoma Multiforme: A Therapeutic Promise for Natural Products.

Glioblastoma multiforme (GBM) continues as one of the most lethal cerebral cancers despite standard therapeutic modalities, such as maximum surgical resection and chemoradiation. The minimal effectiveness of existing therapies necessitates the development of additional drug candidates that could improve the prognosis of GBM patients. Accumulating evidence suggests that calcium (Ca2+) is involved in the processes of cell proliferation, metastasis, angiogenesis, migration, and invasiveness. Therefore, Ca2+ could serve as a crucial regulator of tumorigenesis and a potential treatment target in GBM. In this context, specific natural products are known to modulate Ca2+ signaling pathways implicated in tumor growth, apoptosis, angiogenesis, and development of GBM. Here, the focus is on the function of Ca2+ as a therapeutic target in GBM and reviewing certain natural products that affect the signaling pathways of Ca2+.

Cytokines as potential combination agents with PD-1/PD-L1 blockade for cancer treatment.

Immunotherapy has caused a paradigm shift in the treatment of several malignancies, particularly the blockade of programmed death-1 (PD-1) and its specific receptor/ligand PD-L1 that have revolutionized the treatment of a variety of malignancies, but significant durable responses only occur in a small percentage of patients, and other patients failed to respond to the treatment. Even those who initially respond can ultimately relapse despite maintenance treatment, there is considerable potential for synergistic combinations of immunotherapy and chemotherapy agents with immune checkpoint inhibitors into conventional cancer treatments. The clinical experience in the use of cytokines in the clinical setting indicated the efficiency of cytokine therapy in cancer immunotherapy. Combinational approaches to enhancing PD-L1/PD-1 pathways blockade efficacy with several cytokines such as interleukin (IL)-2, IL-15, IL-21, IL-12, IL-10, and interferon-α (IFN-α) may result in additional benefits. In this review, the current state of knowledge about PD-1/PD-L1 inhibitors, the date in the literature to ascertain the combination of anti-PD-1/PD-L1 antibodies with cytokines is discussed. Finally, it is noteworthy that novel therapeutic approaches based on the efficient combination of recombinant cytokines with the PD-L1/PD-1 blockade therapy can enhance antitumor immune responses against various malignancies.

Quercetin: A promising phytochemical for the treatment of glioblastoma multiforme.

Quercetin, a plant-derived flavonoid, is known for its antitumor and antiproliferative activities. Glioblastoma multiforme (GBM), as a highly aggressive cerebrum tumor, has a poor prognosis that is approximately 12 months despite standard therapy. Therefore, because of the low effectiveness of the current therapeutic strategies, additional medications in combination with chemotherapy and radiotherapy are needed, which could improve the prognosis of GBM patients. Multiple lines of evidence have shown that quercetin regulates many proteins involved in the cellular signal transduction in GBM. In this review, recent findings on the targeting of particular signaling pathways by quercetin and the subsequent effect on the pathogenesis of GBM are presented and discussed.

Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process.

Epithelial-mesenchymal transition (EMT) is a critical process in the development of many tissues and organs in multicellular organisms that its important role in the pathogenesis of metastasis and tumor cell migration has been firmly established. Decreased adhesive capacity, cytoskeletal reorganization, and increased mobility are hallmarks of the EMT. Several molecular mechanisms promote EMT, Including regulation of the levels of specific cell-surface proteins, ECM-degrading enzymes, and altering the expression of certain transcription factors and microRNAs. EMT process is modulated through multiple signaling pathways including the AKT/mTOR pathway. AKT is a key component in numerous processes which was recently shown to regulate the EMT through suppression of the expression of E-cadherin via EMT transcription factors. On the other hand, mTOR complexes can also regulate the EMT through the regulation of cell's actin cytoskeleton by altering the PKC phosphorylation state and direct phosphorylation and activation of Akt. Here we review the effect of AKT and mTOR on EMT and consequently metastasis and cell motility.

The thioredoxin system and cancer therapy: a review.

Thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH are key members of the Trx system that is involved in redox regulation and antioxidant defense. In recent years, several researchers have provided information about the roles of the Trx system in cancer development and progression. These reports indicated that many tumor cells express high levels of Trx and TrxR, which can be responsible for drug resistance in tumorigenesis. Inhibition of the Trx system may thus contribute to cancer therapy and improving chemotherapeutic agents. There are now a number of effective natural and synthetic inhibitors with chemotherapy applications possessing antitumor activity ranging from oxidative stress induction to apoptosis. In this article, we first described the features and functions of the Trx system and then reviewed briefly its correlations with cancer. Finally, we summarized the present knowledge about the Trx/TrxR inhibitors as anticancer drugs.

Recent advances in the clinical development of immune checkpoint blockade therapy.

BACKGROUND: The discovery of immune checkpoint proteins and the mechanisms by which cancer cells utilize them to evade the immune system has transformed our approach to cancer immunotherapy. Checkpoint blockade antibodies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligands such as programmed cell death ligand 1 (PD-L1) have already revolutionized the treatment of multiple types of cancer and have significantly improved treatment and survival outcomes of patients affected by these malignancies. CONCLUSIONS: Herein, we summarize current knowledge about the role of, and the mechanisms underlying PD-1/PD-L1 signaling pathways in antitumor immune responses, with particular emphasis on clinical studies evaluating the efficacy of anti-PD-1/PD-L1 blockade in various tumor types. Preliminary clinical investigations with immune-checkpoint blockers highlight broad opportunities with a high potential to enhance antitumor immunity and, as such, to generate significant clinical responses. These preliminary successes open up new avenues towards efficient therapeutics offered to patients.

Tumor-associated macrophages: role in cancer development and therapeutic implications.

BACKGROUND: Tumor-associated macrophages (TAMs) are known to play important roles in the initiation and progression of human cancers, as well as in angiogenesis. TAMs are considered as main components of the tumor microenvironment. Targeting TAMs may serve as a therapeutic strategy for the treatment of cancer. In this review, the signaling pathways, origin, function, polarization and clinical application of TAMs are discussed. The role of TAMs in tumor initiation, progression, angiogenesis, invasion and metastasis are also emphasized. In addition, a variety of clinical and pre-clinical approaches to target TAMs are discussed. CONCLUSIONS: Clinical therapeutic approaches that show most promise include blocking the extravasation of TAMs along with using TAMs as diagnostic biomarkers for cancer progression. The targeting of TAMs in a variety of clinical settings appears to be a promising strategy for decreasing metastasis formation and for improving patient outcome.

Emerging roles of microRNAs in regulating the mTOR signaling pathway during tumorigenesis.

The mammalian target of rapamycin (mTOR) is a large Ser/Thr protein kinase that belongs to the phosphoinositide 3-kinase (PI3K) family and mediates various physiological and pathological processes, especially cell proliferation, protein synthesis, autophagy, and cancer development. The mTOR expression is transient and tightly regulated in normal cells, but it is overactivated in cancer cells. Recently, several studies have indicated that microRNAs (miRNAs) play a critical role in the regulation of mTOR and mTOR-associated processes, some acting as inhibitors and the others as activators. Although it is still in infancy, the strategy of combining both miRNAs and mTOR inhibitors might provide an approach to selectively sensitizing tumor cells to chemotherapy-induced DNA damage and subsequently attenuating the tumor cell growth and apoptosis.

5'-Adenosine monophosphate-activated protein kinase: A potential target for disease prevention by curcumin.

Curcumin (diferuloylmethane), a yellowish agent extracted from turmeric, is a bioactive compound known for its anti-inflammatory, antiproliferative, antidiabetic, and anticancer activities. Multiple lines of evidence have indicated that curcumin regulates several regulatory proteins in the cellular signal transduction pathway. AMP-activated protein kinase (AMPK) is one of the central regulators of cellular metabolism and energy homeostasis, which is activated in response to increasing cellular adenosine monophosphate/adenosine triphosphate ratio. AMPK plays a critical role in regulating growth and reprogramming metabolism and is linked to several cellular processes including apoptosis and inflammation. Recently, it has been demonstrated that AMPK is a new molecular target affected by curcumin and its derivatives. In this review, we discuss recent findings on the targeting of AMPK signaling by curcumin and the resulting impact on the pathogenesis of proinflammatory diseases. We also highlight the therapeutic value of targeting AMPK by curcumin in the prevention and treatment of proinflammatory diseases, including cancers, atherosclerosis, and diabetes.

Molecular targeting for treatment of human T-lymphotropic virus type 1 infection.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is linked to adult T-cell leukemia-lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and several other disorders. ATLL occurs in approximately 5% of the 15-20 million people infected by HTLV-1 in the world. In general, ATLL is resistant to chemotherapy, which underlines the need for new and effective therapeutic strategies. Previous studies highlighted the role of viral enzymes, responsible for viral replication, and regulatory proteins such as Tax and HBZ in the progression of HTLV-1-associated diseases. There are conflicting reports on the efficacy of current enzyme inhibitors, mainly developed against human immunodeficiency virus (HIV), for treatment of HTLV-1 infection. New treatment approaches including monoclonal antibodies show promising results and exert significant cytotoxic effects on ATLL cells. This manuscript reviews the recent developments in molecular targeting for treatment of HTLV-1 infection.

PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer.

Colorectal cancer (CRC), as a prominent cause of cancer-related deaths, has historically been notable worldwide and many attempts have been made to raise the overall survival of CRC patients. Immune response has long been a question of great interest in a wide range of fields such as cancer therapies and anti-tumor immunity through checkpoint inhibitors, specifically anti PD-1/ PD-L1 interaction, is a new line of research for treatment of CRC patients. Following the successful development of anti-PD-1 for melanoma, renal cell carcinoma, and non-small cell lung cancer, several clinical trials have been conducted on monoclonal antibodies (MAbs) against PD-1 in CRC. There is a growing body of literature that recognizes the importance of anti-PD-1 therapy for MSI (Microsatellite instability) tumors among CRC subtypes. We present a comprehensive knowledge of immune therapy through PD-1/PD-L1 blockade that argues how efficient the process is, in colon cancer carcinoma. In this review, we discuss the responsiveness of immunotherapy on PD-1/PD-L1 blockade and various tactics for overcoming weak responses to these checkpoint inhibitors in CRC. More research using controlled trials is required to enable new discoveries to provide continued success with immune-based therapies and grounds for optimism about the future of CRC patients.

The comparative study of the effects of Fe2 O3 and TiO2 micro- and nanoparticles on oxidative states of lung and bone marrow tissues and colony stimulating factor secretion.

Nowadays, increased use of nanomaterials in industry and biomedicine poses potential risks to human health and the environment. Studying their possible toxicological effects is therefore of great significance. The present investigation was designed to examine the status of oxidative stress induced by nanoparticles (NPs) of ferric oxide (Fe2 O 3 ) and titanium oxide (TiO 2 ) with their micro-sized counterpart on mouse lung and bone marrow-derived normal tissue cells. We assessed the induction of oxidative stress by measuring its indicators such as antioxidant scavenging activity of superoxide dismutase and catalase as well as malondialdehyde concentration. Moreover, colony formation of bone marrow cells was assayed following induction with colony stimulating factor (CSF) from lung cells. NPs had a more potent stimulatory effect on the oxidative stress status than their micron-sized counterparts. In addition, the highest level of oxidative stress derived from TiO 2 NPs was observed in both tissue types. Cotreatment with NPs and the antioxidant α-tocopherol reduced antioxidant activities and membrane lipid peroxidation (LPO) in the lung cells, but increased CSF-induced colony formation activity of bone marrow cells, suggesting that oxidative stress may be the cause of the cytotoxic effects of NPs. It is concluded that free radicals generated following exposure to NPs resulted in significant oxidative stress in mouse cells, indicated by increased LPO and antioxidant enzyme activity and decreased colony formation.