Anticancer Research Articles

Targeting c-Met in Cancer Therapy: Unravelling Structure-Activity Relationships and Docking Insights for Enhanced Anticancer Drug Design.

The c-Met receptor, a pivotal player in oncogenesis and tumor progression, has become a compelling target for anticancer drug development. This review explores the intricate landscape of Structure-Activity Relationship [SAR] studies and molecular binding analyses performed on c-Met inhibitors. Through a comprehensive examination of various chemical scaffolds and modifications, SAR investigations have elucidated critical molecular features essential for the potent inhibition of c-Met activity. Additionally, molecular docking studies have provided invaluable insights into how c-Met inhibitors interact with their target receptor, facilitating the rational design of novel compounds with enhanced efficacy and selectivity. This review highlights key findings from recent SAR and docking studies, particularly focusing on the structural determinants that govern inhibition potency and selectivity. Furthermore, the integration of computational methodologies with experimental approaches has accelerated the discovery and optimization of c-Met inhibitors, fostering the advancement of promising candidates for clinical applications. Overall, this review underscores the pivotal role of SAR and molecular docking studies in advancing our understanding of c-Met inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.

PH-responsive magnetic nanocarrier based on hyaluronic acid-folic acid conjugated Fe3O4 nanoparticles for controlled delivery of imatinib: Isotherms, kinetics, and thermodynamics studies

A novel pH-responsive magnetic nanocarrier was synthesized with hyaluronic acid/folic acid conjugated magnetic nanoparticles and used as a drug carrier for imatinib drug delivery. Magnetic nanoparticles were surface modified with (3-glycidyloxypropyl) trimethoxysilane. Grafting of hyaluronic acid/folic acid on these magnetic nanoparticles was characterized by Fourier-transform infrared spectroscopy, X-ray diffraction, Field emission scanning electron microscopy, thermogravimetric analysis, and vibrating sample magnetometer. The effect of adsorption parameters such as pH, initial concentration, contact time, and adsorbent dosage was examined. The pseudo-second-order model best described the kinetic data, while the Langmuir model best described the isotherm data, indicating physico-sorption and monolayer imatinib adsorption, respectively. Also, thermodynamic experiments showed that the uptake of the drug by the magnetic adsorbent was endothermic and spontaneous. The maximum sorption capacity of unmodified magnetic nanoparticle for imatinib was 6.38 mg/g and for modified magnetic nanoparticles, it was 16.56 mg/g. Imatinib as an anticancer drug, was loaded and the release curve was investigated at pH 5.6 and 7.4 for 6 h. At acidic fluid, the amount of imatinib released increased to 63.01 % compared to physiological fluid with 26.04 % drug release.

Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.

Advancements in therapeutic strategies and combinatorial approaches for cancer management have led to the majority of cancers in the initial stages to be regarded as treatable and curable. However, certain high-grade cancers in the initial stages are still regarded as chronic and difficult to manage, requiring novel therapeutic strategies. In this era of targeted and precision therapy, novel strategies for targeted delivery of drug and synergistic therapies, integrating nanotherapeutics, polymeric materials, and modulation of the tumor microenvironment are being developed. One such strategy is the study and utilization of smart-nano biomedicine, which refers to stimuli-responsive polymeric materials integrated with the anti-cancer drug that can modulate the reactive oxygen species (ROS) in the tumor microenvironment or can be ROS responsive for the mitigation as well as management of various cancers. The article explores in detail the ROS, its types, and sources; the antioxidant system, including scavengers and their role in cancer; the ROS-responsive targeted polymeric materials, including synergistic therapies for the treatment of cancer via modulating the ROS in the tumor microenvironment, involving therapeutic strategies promoting cancer cell death; and the current landscape and future prospects.

Molecular docking and ADME evaluation of plant-based bioactive molecules targeting nonsense-mediated mRNA decay pathway factors to modulate tumorigenesis

Cancer is a global health challenge that requires continuous efforts to discover effective anticancer drugs. Phytochemicals are compounds found in plants that often have medicinal properties. They possess a wide range of bioactive properties, including anticancer activity. Their multiple mechanisms of action in different physiological processes in humans make them promising candidates in the anticancer therapeutics development. The presence of these compounds makes plants valuable resources for traditional medicine and modern pharmaceutical research as well. Natural products from plants and marine sources are being used to find new anticancer agents. In humans, different cellular pathways are involved in the tumorigenesis process. Many studies have shown the role of the nonsense-mediated mRNA decay (NMD) pathway in the process of tumorigenesis. This NMD pathway is controlled by multiple proteins. In this study, we conducted a molecular docking analysis of 50 phytochemicals against the human NMD factor up-frameshit2 (UPF2) protein. The results of the molecular docking experiment and ADME properties indicate that 4 of these molecules (Genistein, Trihydroxyflavone, Baicalein and Epigallocatechin) have the potential to modulate the NMD pathway. Furthermore, these molecules comply with Lipinski's rule of five. The effects of these 4 phytochemicals may be further evaluated using in vitro and in vivo methods for novel anticancer therapeutic development.

Correlation Analysis Among the Chemical Composition and Cytotoxic and Antioxidative Activities of a Tessaria absinthioides Decoction for Endorsing Its Potential Application in Oncology

Historically, botanical preparations have been used to improve human health. Their active ingredients are influenced by multiple factors such as intraspecies variations, environmental conditions, collection time and methods, and the part of the plant used. To ensure the efficiency and safety of these herbal drugs, qualitative and quantitative analyses are required. A Tessaria absinthioides decoction (DETa) was reported as having hypocholesterolemic, anti-inflammatory, cytotoxic, antitumor, and antioxidative properties. This work aimed to analyze DETa by correlating its chemical composition with cytotoxic and antioxidative properties, with the aim of promoting research on it as an anticancer agent. DETa collections (2017, 2018, 2019, and 2022) were analyzed by UHPLC-DAD, UHPLC-DAD-FLD, and UPLC-MS/MS; cytotoxicity was assessed on the MCF-7 breast cancer cell line; antioxidative capacity was evaluated by the DPPH and FRAP methods; and correlation analysis was used to determine biological and chemical markers. The results provide evidence that biological activities were consistent across the collections. Among the quantified compounds, apigenin, naringin, gallocatechin gallate, ginnalin A, myricetin, epicatechin, OH-tyrosol, quercetin, and chlorogenic, tessaric, p-coumaric, vanillic, caffeic, caftaric, ellagic, and rosmarinic acids correlated as bioactive and chemical markers. Moreover, tessaric acid could be established as a species marker. Altogether, these findings add relevant information to DETa properties, encouraging further exploration of its potential application as an anticancer botanical.

The Excellent Chemical Interaction Properties of Poloxamer and Pullulan with Alpha Mangostin on Amorphous Solid Dispersion System: Molecular Dynamics Simulation

Background: Alpha mangostin (AM) has demonstrated significant potential as an anticancer agent, owing to its potent bioactivity. However, its clinical application is limited by poor solubility, which hampers its bioavailability and effectiveness. Amorphous solid dispersion (ASD) presents a promising technique to enhance the solubility and stability of AM. Molecular dynamics simulation offers a rapid, efficient, and precise method to evaluate and optimize ASD formulations before production. Aim of Study: In this study, we conducted molecular dynamics simulations to explore the ASD development of AM with poloxamer and pullulan. Result: Our results revealed that AM–poloxamer complexes exhibit superior interaction characteristics compared to AM–pullulan, with a 1:5 ratio of AM to poloxamer and a cooling rate of 1 °C/ns demonstrating the most favorable outcomes. This combination showed enhanced hydrogen bonding, a more compact molecular structure, and higher stability, making it the optimal choice for ASD formulation. Conclusion: The integration of molecular dynamics simulation into ASD development significantly accelerates the formulation process and provides critical insights into achieving a stable and effective AM dispersion. The AM–poloxamer complex, particularly at a 1:5 ratio with a 1 °C/ns cooling rate, offers the best potential for improving AM solubility and therapeutic efficacy.

DIVERSE SYNTHETIC APPROACHES TO CRAFT IMIDAZOLES - A REVIEW

Imidazoles are five membered heterocyclic ring compounds containing two nitrogen atoms as a part of a five membered ring. Imidazole is a pharmacologically important molecule mainly used as antihypertensive, antiplasmodial, antifungal and anticancer agents etc. It can be synthesized by using a variety of starting materials by different synthesis such as – Debus Radziszewski, Van Leusen, Wallach synthesis to name a few. By altering the starting materials different derivatives of imidazole can be synthesized and show a wide range of pharmacological activites. Hence organic chemists are continuously striving to synthesize novel imidazole derivatives that could show better pharmacological effects. This review article focuses on different types of synthesis available to chemists for this versatile molecule.

Dual Loading of Trans-Cinnamaldehyde and Either Paclitaxel or Curcumin in Chitosan Nanoparticles: Physicochemical Characterization and Biological Evaluation Against MDCK and HeLa Cells

Biopolymer chitosan sub-micron particles (CSMPs) were prepared by the ionic gelation technique crosslinked with sodium tripolyphosphate co-loaded with trans-cinnamaldehyde (TCIN), and either curcumin (CUR) or paclitaxel (PTX). The size of the spherical CSMPs increased from 118 nm to 136 nm and 170 nm after the loading of TCIN and CUR, whereas the loading of PTX led to a slight decrease (114 nm). Polydispersity indexes of all the samples were smaller than 0.4, indicating monodisperse particles. Zeta potential values higher than +40 mV were determined, which is direct proof of the high stability of these nanoparticles. TCIN and PTX release studies in vitro, at pH 6.5 and 7.4, showed a pH dependence on the release rate with a higher value at pH 6.5. However, CUR was not released from CSMPs probably due to strong interactions with CS biopolymer chains. Cytotoxicity studies showed that the systems loaded with TCIN and PTX were more cytotoxic for HeLa cancer cells than for MDCK cells. Moreover, a synergistic effect against HeLa cells was observed for the TCIN-PTX-loaded CSMP samples. The Sensitivity Index indicated that the CSMPs loaded with TCIN have a prospective attraction to carry and release conventional or new chemotherapeutic drugs. This study demonstrates the in vitro efficiency of the obtained drug delivery system, but in vivo studies are necessary to confirm its potential for clinical applications.

Understanding the Anticancer Properties of Honey

Uncontrolled cell growth that possesses the capacity to exhibit malignant behavior is referred to as cancer. The cytotoxic drugs used to fight cancer are associated with several adverse effects and are not always readily available or affordable, especially in developing countries. These issues are in addition to the shortcomings of the current cancer treatment regimen. According to growing research, honey is not cytotoxic to normal cells but is highly and particularly cytotoxic to tumor cells, suggesting that honey may display anticancer effects. Research has shown that honey affects a number of cell signaling pathways; however, at the moment, the precise method is not completely known.

Polo-like kinase 2 targeting as novel strategy to sensitize mutant p53-expressing tumor cells to anticancer treatments.

Polo-like kinase 2 (Plk2) belongs to a family of serine/threonine kinases, and it is involved in tumorigenesis of diverse kind of tissues. We previously reported that Plk2 gene was a transcriptional target of the mutant p53/NF-Y oncogenic complex. Plk2 protein can bind to and phosphorylate mutant p53 triggering an oncogenic autoregulatory feedback loop involved in cancer cell proliferation and chemoresistance. In this study, we aimed to assess whether the specific inhibition of Plk2 kinase activity by the selective TC-S 7005 inhibitor could decrease cell proliferation and migration inhibiting mutant p53 phosphorylation, thus disarming its oncogenic potential. We found that the Plk2 inhibitor treatment sensitized the cells to the irradiation and chemotherapy drugs, thereby overcoming the mutant p53-dependent chemoresistance. Taken together, we provided results that Plk2 could be considered a tractable pharmacological target for cancers expressing mutant p53 proteins. The combined treatment with conventional chemotherapeutic drugs and Plk2 inhibitors may represent a new candidate intervention approach, which may be considered for improving tumor cell sensitivity to DNA damaging drugs. KEY MESSAGES : Missense mutations are present in the TP53 gene in about half of all human cancers and correlate with poor patient outcome. Mutant p53 proteins exert gain of function (GOF) activities in tumor cells such as increased proliferation, genomic instability and resistance to therapies. Polo-like kinase 2 (PLK2) binds and phosphorylates mutant p53 protein strengthening its GOF activities. Pharmacologically targeting PLK2 weakens mutant p53 proteins and sensitizes tumor cells to therapeutic treatments.

Nanocarrier Delivery of Cisplatin and its Patent Studies

Cisplatin, also known as cis-(diammine) dichloridoplatinum (II) or CDDP, is frequently used as first-line chemotherapy in head, neck, and lung malignancies. It can be given as a single agent or in conjunction with radiation therapy and/or other anti-cancer chemotherapeutic agents. Now, experiences based on PEGylated liposome-based nano-formulations AroplatinTM, LipoplatinTM, and SPI-077 are undergoing clinical trials. These cisplatin drug delivery systems resolve issues like poor solubility in water, drug resistance, and toxicity by using nanocarrier systems. The above-cited nano-delivery technologies for cisplatin have been extensively described in numerous pieces of literature existing in various databases. Essentially, this evaluation gives a severe focus on newer information, invented news, and up-to-date articles regarding various carrier systems for CDDP and the newer patents of this drug formulation.

Psoriasis Vulgaris (PV) Exacerbation in Acute Myeloid Leukemia (AML) Patient Treated with Cytarabine/Daunorubicin (C/D)

Adverse reactions associated with chemotherapeutic agents to treat acute leukemia such as cytarabine and daunorubicin (C/D) have been reported regularly, however, psoriasis vulgaris is a rare adverse event. We report a 46-year-old Indonesian man presented with multiple erythema scaly plaques on his trunk for one month. He was diagnosed with acute myeloid leukemia (AML) 4 months ago, and received remission-induction chemotherapy for AML with a high-dose combination of C/D.

Rapid Hemostasis Tumor In Situ Hydrogel Vaccines for Colorectal Cancer Chemo-Immunotherapy.

Due to the high heterogeneity and the immunosuppressive microenvironment of tumors, most single antigen tumor vaccines often fail to elicit potent antitumor immune responses in clinical trials, resulting in unsatisfactory therapy effects. Hence, personalized tumor vaccines have become a promising modality for cancer immunotherapy. Here, we have developed a tumor in situ hydrogel vaccine (AH/DA-OR) capable of rapid hemostasis for personalized tumor immunotherapy, composed of dopamine-grafted hyaluronic acid (HA/DA) combined with sodium alginate (ALG), with coloaded oxaliplatin (OXA) and resiquimod (R848). The ALG and HA framework imparts excellent biocompatibility to the hydrogel, and dopamine (DA) modification endows it with rapid hemostatic functionality. Following local peritumor injection of AH/DA-OR into the tumor, the in situ hydrogel vaccine achieved the sustained release of the chemotherapeutic agent, OXA, inducing immunogenic cell death in tumor cells and effectively releasing personalized tumor-associated antigens to activate immune responses. Simultaneously, local R848 adjuvant sustained release at the tumor site enhanced immune responses, minimized drug side effects, and amplified immunotherapy effects. Finally, the hydrogel vaccine effectively activated host immune responses to suppress CT26 colorectal cancer growth in vivo, also exhibiting superior inhibition of untreated tumor growth at distant sites. This strategy of rapid hemostasis of tumor in situ hydrogel vaccine holds significant clinical potential and provides a paradigm for achieving secure and robust immunotherapy.

Development and validation of an UPLC-ESI-MS/MS method for simultaneous quantification of antineoplastic agents and their metabolites in human plasma after unintentional exposure.

Cyclophosphamide, daunorubicin, epirubicin, doxorubicin and paclitaxel are commonly used drugs in cancer treatment. However, there are no methods available enabling simultaneous measurement of these compounds and their metabolites in human plasma. Our aim was to develop and validate a sensitive method for simultaneous quantification of multiple antineoplastic drugs and their major metabolites in plasma. Solid phase extraction with Oasis PRiME HLB cartridges was used for sample clean-up. The samples were separated on an Acquity UPLC BEH C18 column, ionised by electrospray ionisation and detected with tandem mass spectrometry. The method was validated based on selectivity, extraction efficiency, matrix effect, process efficiency, linearity, sensitivity, precision and accuracy. The established LLOQs were 0.05ng/mL (cyclophosphamide), 30ng/mL (4-oxo-cyclophosphamide), 0.3ng/mL (doxorubicin, daunorubicinol), 0.7ng/mL (epirubicin, epirubicinol, doxorubicinol), 1ng/mL (daunorubicin and paclitaxel) and 5ng/mL (6-alpha-hydroxypaclitaxel). Afterwards, the method was tested in a real-life, unintentional exposure setting. Twenty-two plasma samples of matched maternal and cord blood pairs from pregnant cancer patients treated with chemotherapy were analysed. This resulted in two positive samples, with cyclophosphamide concentrations up to 0.37ng/mL. The validated method is now ready to be applied in the field.

Expression Profiling Identified TRPM7 and HER2 as Potential Targets for the Combined Treatment of Cancer Cells

TRPM7 is a divalent cation-permeable channel that is highly active in cancer cells. The pharmacological inhibitors of TRPM7 have been shown to suppress the proliferation of tumor cells, highlighting TRPM7 as a new anticancer drug target. However, the potential benefit of combining TRPM7 inhibitors with conventional anticancer therapies remains unexplored. Here, we used genome-wide transcriptome profiling of human leukemia HAP1 cells to examine cellular responses caused by the application of NS8593, the potent inhibitor of the TRPM7 channel, in comparison with two independent knockout mutations in the TRPM7 gene introduced by the CRISPR/Cas9 approach. This analysis revealed that TRPM7 regulates the expression levels of several transcripts, including HER2 (ERBB2). Consequently, we examined the TRPM7/HER2 axis in several non-hematopoietic cells to show that TRPM7 affects the expression of HER2 protein in a Zn2+-dependent fashion. Moreover, we found that co-administration of pharmacological inhibitors of HER2 and TRPM7 elicited a synergistic antiproliferative effect on HER2-overexpressing SKBR3 cells but not on HER2-deficient MDA-MB-231 breast cancer cells. Hence, our study proposes a new combinatorial strategy for treating HER2-positive breast cancer cells.

The signature of SARS-CoV-2-related genes predicts the immune therapeutic response and prognosis in breast cancer

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an exceptionally contagious single-stranded RNA virus with a strong positive contagion. The COVID-19 pandemic refers to the swift worldwide dissemination of SARS-CoV-2 infection, which began in late 2019. The COVID-19 epidemic has disrupted many cancer treatments. A few reports indicate that the prevalence of SARS-CoV-2 has disrupted the treatment of breast cancer patients (BCs). However, the role of SARS-CoV-2 in the occurrence and prognosis of BC has not been elucidated. Here, we applied bioinformatics to construct a prognostic signature of SARS-CoV-2-related genes (SCRGs). Specifically, weighted gene co-expression network analysis (WGCNA) was utilized to extract co-expressed genes of differentially expressed genes (DEGs) in breast cancer and SCRGs. Then, we utilized the least absolute shrinkage and selection operator (LASSO) algorithm and univariate regression analysis to screen out three hub genes (DCTPP1, CLIP4 and ANO6) and constructed a risk score model. We further analyzed tumor immune invasion, HLA-related genes, immune checkpoint inhibitors (ICIs), and sensitivity to anticancer drugs in different SARS-CoV-2 related risk subgroups. In addition, we have developed a nomination map to expand clinical applicability. The results of our study indicate that BCs with a high-risk score are linked to negative outcomes, lower immune scores, and reduced responsiveness to anticancer medications. This suggests that the SARS-CoV-2 related signature could be used to guide prognosis assessment and treatment decisions for BCs.

Aminoacid functionalised magnetite nanoparticles Fe3O4@AA (AA = Ser, Cys, Pro, Trp) as biocompatible magnetite nanoparticles with potential therapeutic applications

Magnetic nanoparticles (MNPs) are of great interest for their wide applications in biomedical applications, such as bioimaging, antitumoral therapies, regenerative medicine, and drug delivery. The work aimed to obtain biocompatible magnetite nanoparticles coated with amino acids of the general formula Fe3O4@AA (AA = L-tryptophan, L-serine, L-proline and L-cysteine) for potential therapeutic application in anticancer drug delivery. The obtained materials were characterised using XRD, FTIR, DLS analysis, SEM, thermogravimetry (TG), differential scanning calorimetry (DSC), and UV–vis spectroscopy. The photocatalytic, cytotoxic and antimicrobial activity tests of the obtained materials were carried out. The choice of amino acid determines the properties of the material and its future use, for example, Fe3O4@Cys supports radical production, which may increase the efficiency of catalytic degradation, while tryptophan captures radicals, which may be an advantage in several biomedical applications. Fe3O4@Trp exhibited good antimicrobial activity (MBEC and MIC) against E. coli ATCC 25922, P. aeruginosa ATCC 27853 and C. albicans ATCC 10231 while Fe3O4@Pro exhibited the best results against S. aureus ATCC 25923.

Tumor-targeted glutathione oxidation catalysis with ruthenium nanoreactors against hypoxic osteosarcoma

The majority of anticancer agents have a reduced or even complete loss of a therapeutic effect within hypoxic tumors. To overcome this limitation, research efforts have been devoted to the development of therapeutic agents with biological mechanisms of action that are independent of the oxygen concentration. Here we show the design, synthesis, and biological evaluation of the incorporation of a ruthenium (Ru) catalyst into polymeric nanoreactors for hypoxic anticancer therapy. The nanoreactors can catalyze the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) in hypoxic cancer cells. This initiates the buildup of reactive oxygen species (ROS) and lipid peroxides, leading to the demise of cancer cells. It also stimulates the overexpression of the transient receptor potential melastatin 2 (TRPM2) ion channels, triggering macrophage activation, leading to a systemic immune response. Upon intravenous injection, the nanoreactors can systemically activate the immune system, and nearly fully eradicate an aggressive osteosarcoma tumor inside a mouse model.

Advancements in nanotheranostics for glioma therapy.

Gliomas are brain tumors mainly derived from glial cells that are difficult to treat and cause high mortality. Radiation, chemotherapy, and surgical excision are the conventionaltreatments for gliomas. Patients who have surgery or have undergone chemotherapy for glioma treatment have poor prognosis with tumor recurrence. In particular, for glioblastoma,the 5-year averagesurvival rateis 4-7%, and the median survival is 12-18months. Anumber of issues hinder effective treatmentsuch as, poor surgical resection, tumor heterogeneity, insufficient drug penetration across the blood-brain barrier, multidrug resistance, and difficulties with drug specificity. Nanotheranostic-mediated drug delivery is becoming a well-researched consideration, and an efficient non-invasive method for delivering chemotherapeutic drugs to the target area. Theranostic nanomedicines, which incorporate therapeutic drugs and imaging agents forpersonalized therapies, can be used for preventing overdose of non-responders. Through the identification of massive and complicated information from next-generation sequencing, machine learning enables for precise prediction of therapeutic outcomes and post-treatment management for patients with cancer. This article gives a thorough overview of nanocarrier-mediated drug delivery with a brief introduction to drug delivery challenges. In addition, this assessment offers a current summary of preclinical and clinical research on nanomedicines for gliomas. In the future, nanotheranostics will provide personalized treatment for gliomas and other treatable cancers.

Influence of Nanomedicine as a Smart Weapon on Multidrug Resistance in Cancer Therapy.

Cancer is the leading cause of death worldwide. The effectiveness of chemotherapy in cancer patients is still significantly hampered by Multidrug Resistance (MDR). Tumors exploit the MDR pathways to invade the host and limit the efficacy of chemotherapeutic drugs that are delivered as single drugs or combinations. Further, overexpression of ATP-binding Cassette transporter (ABC transporter) proteins augments the efflux of chemotherapeutic drugs and lowers their intracellular accumulation. Recent progress in the development of nanotechnology and nanocarrier-based drug delivery systems has shown a better perspective with respect to the improvement of cancer chemotherapy. Nanoparticles/nanomaterials are designed to target the immune system and tumor microenvironment of cancer cells for a variety of cancer treatments in order to improve bioavailability and reduce toxicity. This review elucidates the successful use of nanomaterials for cancer therapy and addressing the MDR and throws some light on the present obstacles impeding their translation to clinical use.