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Bone cancer induces behavioral hypersensitivity. a, b Intratibial inoculation with Walker 256 mammary gland carcinoma cells (4 × 10⁵) induces significant mechanical allodynia (a) and thermal hyperalgesia (b) in the ipsilateral hindvpaw. c Intratibial inoculation with Walker 256 mammary gland carcinoma cells induces spontaneous flinches in the hind paw ipsilateral to the affected limb. The number of times the hind paw was counted per 5 min during a 10 min observation period, and the average number of flinches per 5 min were calculated. **p < 0.01 versus sham rats
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Bone pain associated with advanced tumor metastasis is the most severe threat to life quality of patients. Highly efficient and low-toxic therapeutics is of urgent need for this complication. Bone tumor metastasis was established by direct bone inoculation of Walker 256 mammary gland carcinoma cells. Bone nociception was measured by mechanical allo...
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Introduction:
Cancer-induced bone pain (CIBP) is acknowledged as a multifactorial chronic pain that tortures advanced cancer patients, but existing treatment strategies for CIBP have not been satisfactory yet. Investigators have demonstrated that the activation of α7-nAChRs exerts analgesic effects in some chronic pain models. However, the role of...
Citations
... The TMP moiety is found in many natural alkaloids with important biological properties such as Podophyllotoxin, Colhicine, and Combretastatin A-4 (CA-4). Podophyllotoxin [54], derived from Podophyllum peltatum, exhibits antimitotic activity by interfering with microtubule function, making it useful in the treatment of certain skin conditions and as a precursor for semisynthetic anticancer drugs like etoposide and teniposide [55,56]. Colchicine is a plant-derived alkaloid inhibiting microtubule polymerization, which disrupts mitosis and inflammatory processes [57]. ...
This study demonstrates the synthesis of five novel quaternary ammonium aldimines through a two-step synthetic route involving a condensation reaction between 4-pyridincarboxyaldehyde and 3,4,5-trimethoxyaniline, followed by the quaternization of the pyridine N-atom with various aromatic α-bromo ketones. The newly obtained compounds underwent characterization for both purity and molecular structure, utilizing HR-MS, 1D, and 2D NMR spectroscopy in solution, as well as a comparison between single-crystal and powder X-ray analyses in a solid state. The thermal behavior of the studied compounds was evaluated using differential scanning calorimetry (DSC). The antioxidant properties of the compounds were assessed through DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging and ferric-reducing antioxidant power (FRAP) assays, employing Trolox as a standard. The performed in vitro antibacterial screening indicates a selective antibacterial activity against Gram-negative K. pneumoniae and P. aeruginosa, while no such activity is detected for Gram-negative E. coli and Gram-positive S. aureus.
... (2) Pain induced during tumor treatment (such as surgery, radiotherapy, and chemotherapy), including radiation neuritis, dermatitis, and tissue necrosis caused by the leakage of chemotherapy drugs outside the blood vessels, are mainly nociceptive and neuropathic pain syndromes [127,128]. Opioids are effective in preventing this type of pain [136,137]. (3) Another cause of pain in patients with cancer is chronic non-cancer pain, which is caused by persistent stimulation of the nervous system and pathological changes [129,130]. The duration of chronic noncancerous pain may be longer than the healing period of the tumor and may persist even after the noxious stimulus is eliminated [131]. ...
... This has been confirmed in inflammatory and neuropathic pain [28,136]. Correspondingly, progress has been made in understanding the contribution of P2X7R to cancer pain [4,137,138] (Fig. 3). Studies have shown that the P2X7R antagonist BBG or small interfering RNA targeting P2X7R inhibit the expression of P2X7R in the rostral ventromedial nucleus (RVM), significantly reducing the expression levels of 5-HT and Fos in the spinal cord, and reduce the pain behavior in rats with tumors [139]. ...
Numerous studies have revealed that the ATP-gated ion channel purinergic 2X7 receptor (P2X7R) plays an important role in tumor progression and the pathogenesis of cancer pain. P2X7R requires activation by extracellular ATP to perform its regulatory role functions. During tumor development or cancer-induced pain, ATP is released from tumor cells or other cells in the tumor microenvironment (such as tumor-associated immune cells), which activates P2X7R, opens ion channels on the cell membrane, affects intracellular molecular metabolism, and regulates the activity of tumor cells. Furthermore, peripheral organs and receptors can be damaged during tumor progression, and P2X7R expression in nerve cells (such as microglia) is significantly upregulated, enhancing sensory afferent information, sensitizing the central nervous system, and inducing or exacerbating pain. These findings reveal that the ATP-P2X7R signaling axis plays a key regulatory role in the pathogenesis of tumors and cancer pain and also has a therapeutic role. Accordingly, in this study, we explored the role of P2X7R in tumors and cancer pain, discussed the pharmacological properties of inhibiting P2X7R activity (such as the use of antagonists) or blocking its expression in the treatment of tumor and cancer pain, and provided an important evidence for the treatment of both in the future.
... On the other hand, teniposide, a chemotherapeutic agent that targets DNA topoisomerase II, has been primarily used for treatment of acute lymphoblastic leukemia, lymphoma, and brain cancer in children [38]. However, the drug's efcacy has also been studied in other diferent types of solid tumors [39][40][41], with the resultant data suggesting that it may inhibit tumor growth through other targets. Tis also suggests that the drug might have multiple molecular targets, and the discovery of new therapeutic targets for the drug is essential to broaden new indications. ...
Purpose:
Esophageal squamous cell cancer (ESCC) is a deadly malignant tumor characterized by an overall 5-year survival rate below 20%, with China accounting for approximately 50% of all cases worldwide. Our previous studies have demonstrated that high integrin-linked kinase (ILK) expression plays a key role in development and progression of ESCC both in vitro and in vivo. Here, we employed the drug repurposing approach to identify a novel FDA-approved anticancer inhibitor against ILK-induced tumorigenesis and progression.
Methods:
We screened the ZINC15 database and predicted the molecular docking ability among FDA-approved and publicly available drugs to ILK and then performed computational docking and visual inspection analyses of the top 10 ranked drugs. Two computer-based virtual screened drugs were evaluated in vitro for their ability to directly bind purified ILK by surface plasmon resonance. Cytotoxicity of the two candidate drugs was validated in vitro using CCK-8 and LDH assays.
Results:
We initially selected the top 10 compounds, based on their minimum binding energy to the ILK crystal, after molecular docking and subjected them to further screening. Taking the binding energy of -10 kcal/mol as the threshold, we selected two drugs, namely, nilotinib and teniposide, for the wet-lab experiment. Surface plasmon resonance (SPR) revealed that nilotinib and teniposide had equilibrium dissociation constant (KD) values of 6.410E - 6 and 1.793E - 6, respectively, which were lower than 2.643E - 6 observed in ILK-IN-3 used as the positive control. The IC50 values for nilotinib and teniposide in ESCC cell lines were 40 μM and 200-400 nM, respectively. Results of the CCK-8 assay demonstrated that both nilotinib and teniposide significantly inhibited proliferation of cells (P < 0.01). LDH results revealed that both drugs significantly suppressed the rate of cell death (P < 0.01).
Conclusion:
The drug repositioning procedure can effectively identify new therapeutic tools for ESCC. Our findings suggest that nilotinib and teniposide are efficacious inhibitors of ILK and thus have potential to target ILK-mediated signaling pathways for management of ESCC.
... Its derivatives also act as excellent anticancer aspirants for future chemotherapies [1][2][3][4][5]. Similar to etoposide [6], teneposide [7] drugs have been proven to be potential antitumor drugs in clinical use; NPF [8] and GL-331 [9] have been under clinical trials. However, their therapeutic efficacy is often limited to their undesirable secondary effects, for example, gastrointestinal toxicity, neurotoxicity, hair loss, bone marrow suppression, etc., as well as the development of resistance by cancer cells [3]. ...
Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-N-sulfonyl amidine hybrids (4a–4v, 5a–5f) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF3 group performed best (IC50: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC50 values.
... In addition, other small molecules including vincristine, teniposide, etoposide, methotrexate, podophyllotoxin and others were also predicted in this study. Some of these small molecules such as vincristine and teniposide have so far been used for antitumor therapy (96,97), and these small molecules may play certain roles in combating LUAD. ...
Background:
Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer (LC). However, the early-stage diagnostic rate is still low, and the 5-year overall survival (OS) rate remains poor. The present study aimed to identify critical genes as diagnostic and prognostic markers and small-molecule drugs for combating LUAD using a systematic bioinformatics analysis.
Methods:
Five gene expression profiling datasets were systematically integrated and analyzed. First, gene coexpression modules were identified, and differentially expressed genes (DEGs) were screened. Second, the functional changes of these DEGs were systematically investigated. Third, the protein-protein interaction network, high correlation module and key genes were identified. Fourth, prognosis and diagnostic analyses were performed. Fifth, small-molecule drugs were predicted for guiding LUAD therapy.
Results:
Finally, 12-gene and 2-gene signatures were identified as diagnostic and prognostic markers. The areas under the curves (AUCs) of two signatures associated with 3-year survival were 0.686 and 0.603, respectively. The AUCs of two signatures were over 95% and 94% in diagnostic model, separately. Eleven small-molecule drugs were found and irinotecan was simultaneously predicted in three drug databases.
Conclusions:
The present study identified some key dysregulated genes involved in LUAD and potential drugs by a comprehensive analysis, which provides novel insights into the pathological mechanism involved in LUAD and may shed light on the diagnosis, prognosis and treatment of LUAD patients.
... Many P2X7 receptor antagonists or inhibitors are used as effective analgesics for cancer-induced bone pain by suppressing the release of pro-inflammatory cytokines like TNFα and IL-18 into the tumor microenvironment. Published literature has suggested the P2X7 receptor's role in both inflammatory and neuropathic bone pain (Falk et al., 2015;Yan et al., 2018). ...
P2X7 receptor, a purinergic receptor family member, is abundantly expressed on many cells, including immune, muscle, bone, neuron, and glia. It acts as an ATP-activated cation channel that permits the influx of Ca2+, Na+ and efflux of K+ ions. The P2X7 receptor plays crucial roles in many physiological processes including cytokine and chemokine secretion, NLRP3 inflammasome activation, cellular growth and differentiation, locomotion, wound healing, transcription factors activation, cell death and T-lymphocyte survival. Past studies have demonstrated the up-regulation and direct association of this receptor in many pathophysiological conditions such as cancer, diabetics, arthritis, tuberculosis (TB) and inflammatory diseases. Hence, targeting this receptor is considered a worthwhile approach to lessen the afflictions associated with the disorders mentioned above by understanding the receptor architecture and downstream signalling processes. Here, in the present review, we have dissected the structural and functional aspects of the P2X7 receptor, emphasizing its role in various diseased conditions. This information will provide in-depth knowledge about the receptor and help to develop apt curative methodologies for the betterment of humanity in the coming years.
Different studies have confirmed P2X7 receptor-mediated inflammatory mediators play a key role in the development of pain. P2X7 receptor activation can induce the development of pain by mediating the release of inflammatory mediators. In view of the fact that P2X7 receptor is expressed in the nervous system and immune system, it is closely related to the stability and maintenance of the nervous system function. ATP activates P2X7 receptor, opens non-selective cation channels, activates multiple intracellular signaling, releases multiple inflammatory cytokines, and induces pain. At present, the role of P2X7 receptor in inflammatory response and pain has been widely recognized and affirmed. Therefore, in this paper, we discussed the pathological mechanism of P2X7 receptor-mediated inflammation and pain, focused on the internal relationship between P2X7 receptor and pain. Moreover, we also described the effects of some antagonists on pain relief by inhibiting the activities of P2X7 receptor. Thus, targeting to inhibit activation of P2X7 receptor is expected to become another potential target for the relief of pain.
Background
Bone cancer pain (BCP) seriously affects patient’s quality of life, which remains a difficult clinical problem, lacking effective drugs for treating it. The inflammation in the spinal cord involves the pathogenesis of BCP. The inhibition of spinal phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or spinal P2X7 receptor (P2X7R) has previously been shown to alleviate BCP. Naringenin (NAR) has analgesic role and anti-inflammatory property.Objective
The present study investigated the protection of NAR against BCP and explored whether the inhibition of spinal inflammation and the blockade of spinal P2X7R/PI3K/AKT signaling involved in this protection.ResultNAR significantly alleviated mechanical allodynia (the increase of paw withdrawal threshold in Von Frey test) and thermal hyperalgesia (the increase of paw withdrawal latency in Hargreaves test) in BCP rats. Additionally, NAR inhibited inflammatory cytokines (the reduced levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were measured using Elisa assay) and down-regulated P2X7R/PI3K/AKT signaling (the decreased P2X7R expression, the reduced ratios of phosphorylated (p)-PI3K/PI3K and p-AKT/AKT, which were detected Western blot) in the spinal cord of BCP rats.ConclusionNAR alleviated BCP through inhibiting inflammatory cytokines and down-regulating P2X7R/PI3K/AKT signaling in the spinal cord of rats. These findings revealed that NAR, as an effective agent against BCP, may provide an effective approach in the management of bone cancer patients.Graphic abstract
