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Clinical Cancer Drugs - Online First
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Biomaterials used to Deliver Drugs for Colon Cancer Management
Authors: Namita Badoniya and Manu SharmaAvailable online: 24 December 2024More LessDespite the major advancements in cancer treatment, colon cancer (CC) is still one of the most lethal malignancies worldwide. Among various type of cancer, it is the third largest prevailing kind of cancer affecting both men and women equally. Metastatic development is particularly common in individuals with advanced stages and frequently associated with subpar response of chemotherapy and severe morbidity. The unfavorable effects of intense chemotherapy on normal cells and emergence of multidrug resistance are the two main reasons for treatment failure. Recent research in nanotechnology enables the use of advanced natural and synthetic biomaterials alone or in combination to target cancer cells with anticancer medications without affecting healthy cells. Anticancer drug laden nanocarriers improve the drug distribution, bioavailability and accumulation of cytotoxic therapeutic concentration at tumor site along with reduced side effects. Additionally, upon oral administration, polymeric vehicles shield the medication from premature release, degradation in upper gastrointestinal tract and facilitate controlled release at cancerous site of colon. Here, we primarily focus on the present situation and possible advantages of polymeric biomaterials either owned or in conjunction with other therapeutics to develop ideal drug carrier systems to treat colon carcinoma.
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Efficacy Assessment of Sulfated Flavanol Functionalized Silver Nanoparticles against MCF-7 Breast Cancer
Authors: Shweta Rajawat, B. Ramachandran and M.M. MalikAvailable online: 02 December 2024More LessAimThe present research work aims to formulate a cost-effective and less toxic drug for specific and selective delivery at the tumor site.
BackgroundExisting therapeutics, such as chemo, surgery, etc., for fast-paced MCF-7 breast cancer, still face challenges, especially due to their toxic side effects. The unique properties of metal nanoparticles embedded in anti-oxidant plant polymers have sparked great interest in the formulation of less toxic-targeted drugs for cancer cure.
ObjectiveThe present work aims to synthesize a targeted formulation of colloidal nanosilver by surface engineering of silver nanoparticles using plant polymers in electrolytic deposition technique, developed indigenously at the institute lab.
MethodsA current is passed through an elctrolyte, AgNO3, which splits it into ions. The positive ions of Ag deposit over LDPE wrapped carbon cathode and negative ion, NO3, is liberated. Ag+ ions get capped in-situ. These surface-modified silver nanoparticles formulate a colloidal solution. UV-visible and FTIR spectroscopy, TEM-EDX, and XRD were used to validate as-prepared formulation and in vivo human tumor xenograft model in NOD-SCID mouse for efficacy against MCF-7 breast cancer.
ResultsThe as-synthesized formulation consists of pure spherical poly-dispersed silver nanoparticles of average size 5.4 nm, coated with sulphated flavanols. The efficacy evaluation reported that it significantly, T/C = 0.53, reduced tumor volumes with a 100% survival rate and change in animal body weight <4 gms.
ConclusionThe as-synthesized formulation can be used as a potential neo-adjuvant or adjuvant drug along with existing therapeutics for MCF-7 breast cancer, significantly reducing the toxicity and cost.
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PROTAC and PROTAB: Revolutionizing Cancer Therapy by Targeted Protein Degradation
Authors: Swati Verma, Sarvesh Paliwal and Debashish ParamanickAvailable online: 15 November 2024More LessChemotherapeutic strategies that target irregularly produced or mutant proteins using monoclonal antibodies (mAbs) and tiny molecular inhibitors have been extensively employed to target cancer. However, because most intracellular proteins lack antigens or active sites with which mAbs or SMIs can engage, they have not been considered druggable targets. After extensive research, PROTACs (Proteolysis Targeting chimaeras) have become a promising way to work with proteins. Scaffolding proteins and transcription factors may also be targeted. The present targets of PROTACs include kinases like CDKs and RTKs, overexpressed oncogenic proteins like AR and BRDs, cancer-driven mutant proteins like EGFR, and disease-relevant fusion proteins like NPM/EML4-ALK and BCR-ABL. The inability of small-molecule intracellular degraders to enter cells and their low bioavailability can also be circumvented with PROTABs. The use of multispecific binding proteins is an improved way to target the breakdown of membrane-bound and cell-surface proteins.
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Revolutionizing Glioblastoma Immunotherapy Conquering Transport and Biological Challenges, Innovating Combinatorial Approaches for Unprecedented Treatment Success
Authors: Shatrudhan Prajapati and Shikha YadavAvailable online: 11 November 2024More LessGlioblastomas are the most common primary brain cancer and present many challenges in treatment, with the current standard-of-care treatments yielding a median survival rate of less than 15 months. While immunotherapy against cancer has been very effective in some cancers, its application in glioblastoma has been limited so far. The following review touches upon some of the critical challenges associated with successful immunotherapy in glioblastoma, covering transport-related obstacles presented by the blood-brain barrier, biological complexity within the central nervous system, and the interplay between glioblastoma and immune cells. Ongoing clinical trials testing the efficacy of different immunotherapeutic strategies, including immune checkpoint blockade, vaccination, and adoptive cell transfer, are discussed. These strategies are inherently challenged by the low immunogenicity of glioblastoma, the unique immune-protective mechanisms of the immune system within the CNS, and the predominant features of the immune-suppressive tumor microenvironment. Current therapeutic modalities reviewed include surgical resection, radiation therapy, and temozolomide-based chemotherapy, with discussions on new forms of approaches to enhance immune activation: vaccines, oncolytic viruses, and adoptive cell therapies such as CAR T cells and NK cells. The perpetual problem of resistance to immunotherapy underlines the need for combination strategies and precise testing within advanced in-vitro and animal tumor models, considering the large variability in glioblastomas.
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Investigation of Novel Quinoline Derivatives Targeting Epidermal Growth Factor Receptors as Anticancer Agents a Computational Approach
Available online: 07 November 2024More LessBackgroundNewer chemical entities are created and synthesis has been made feasible by a variety of computer-aided drug design (CAAD) techniques. In addition to facilitating the visualisation of the ligand-target binding process, the application of in silico methodologies and structure-based drug design (SBDD) allows for the prediction of receptor affinities and significant binding pocket locations.
ObjectiveThe goal of the current study was to identify new quinoline derivatives by computational methods specially designed to bind the EGFR receptor in the treatment of breast cancer.
Materials and MethodsChemAxon Marvin Sketch 5.11.5 was used to create derivatives of quinolines. The admetSAR online web tools and SwissADME were utilised to forecast the toxicity and pharmacokinetic characteristics of several substances. A multitude of software programmes, such as Autodock 1.1.2, MGL Tools 1.5.6, Procheck, Protparam ExPasy tool, PyMOL, and Biovia Discovery Studio Visualizer v20.1.0.19295 were also employed to ascertain the ligand-receptor interactions between quinoline derivatives and the target receptor (PDB -5GNK).
ResultAlmost all components were shown to be less hazardous, orally consumable and to have the appropriate pharmacokinetic characteristics based on in silico study. All newly generated derivative compounds have higher docking scores when compared to the widely used medication sorafenib.
ConclusionInteractions with quinoline analogues boost binding energy and the number of H-bonds produced, making them a suitable place to start when creating compounds for further exploration. The quinoline moiety increases its potential as a novel therapy alternative for breast cancer and could facilitate more comprehensive in vivo, in vitro, chemical-based, and pharma studies by medicinal chemists.
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Synergistic Action of Thymol-citral is Associated with Cell Cycle Arrest and Intracellular ROS Generation in A549 Cells
Available online: 24 October 2024More LessObjectiveNSCLC is the predominant form of lung cancer, often exhibiting resistance to chemotherapy. Thymol and citral have shown promise as anticancer agents in different cancer cell lines but have not been evaluated in combination against NSCLC. Hence, we planned to investigate the anticancer effect of thymol-citral combination and explore its mechanisms of action against A549 cells.
MethodsA549 cells were exposed to varying concentrations of thymol and citral, alone and in combination. Cell proliferation, plasma membrane integrity, apoptotic markers, reactive oxygen species (ROS) levels, cell cycle distribution, senescence induction, and migration potential were assessed. Additionally, in vitro safety was evaluated in human bronchial epithelial cells (HBECs) and human red blood cells (RBCs).
ResultsThymol and citral showed synergistic action against A549 cells, with a CI value of 0.75. After 24 h, they induced apoptosis, caused G0/G1 phase arrest, and increased ROS levels, suggesting oxidative stress as the mechanism. This combination also induced cell senescence, significantly inhibited A549 cell migration, and was non-toxic to human RBCs and HBECs.
ConclusionOverall, the thymol-citral synergistic combination was found to be a safe and effective therapy option for non-small cell lung cancer.
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PNU-74654 Enhanced the Antiproliferative Activity of Gemcitabine by Targeting Wnt/β-Catenin Pathway in Pancreatic Cancer
Available online: 21 October 2024More LessBackgroundThe Wnt/beta-catenin pathway is one of the pathways that is deregulated in pancreatic cancer and is reported to be associated with a poor prognosis. This indicates the need for the identification of novel agents to improve the efficacy of current therapy or have an improved efficacy. Therefore, in the present study, we explored the anticancer activity of PNU-74654 alone or in combination with gemcitabine in 2 and 3-dimensional cell culture models of pancreatic cancer.
MethodsThe MTT assay was carried out to determine the viability of PC cancerous cells (PCCs), while the cytotoxicity of this agent was evaluated in a 3D cell culture model (spheroid). The effects of PNU-74654 were investigated in established cell migration/invasion assays.
ResultsThe expression of candidate genes affecting the cell cycle, migration, and Wnt/b-catenin pathway was evaluated at mRNA and/or proteins by RT-PCR or Western blot. PNU-74654 inhibited the cell growth at IC50 of 122 ± 0.4 umol/L and had a synergistic effect on the antiproliferative properties of gemcitabine by modulating the Wnt pathway. The PNU-74654/gemcitabine combination reduced the migratory and invasiveness of PC cells, compared to control cells, through perturbation of E-cadherin.
ConclusionOur findings demonstrate the profound antitumor properties of PNU-74654 in in vitro models of pancreatic cancer, supporting further in vivo studies to evaluate the therapeutic impact of this novel therapy to target the Wnt pathway in the treatment of pancreatic cancer.
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