scholarly journals Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action

2016 ◽  
Vol 7 (3) ◽  
pp. 2381-2391 ◽  
Author(s):  
Raji Raveendran ◽  
Jeremy Phillip Braude ◽  
Ezequiel Wexselblatt ◽  
Vojtech Novohradsky ◽  
Olga Stuchlikova ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mechanisms Of Action ◽  
Cytotoxic Agents ◽  
Cytotoxic Agent ◽  
Axial Ligands ◽  
Cellular Pathways ◽  
Derivatives Of

The Pt(iv) derivative of cisplatin,ctc-[Pt(NH3)2(PhB)2Cl2], is a p53 independent very potent cytotoxic agent that kills cancer cells by triggering various cellular pathways.

scholarly journals Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

2019 ◽  
Vol 5 (6) ◽  
pp. 429-439 ◽  
Author(s):  
Beata Guzow-Krzemińska ◽  
Katarzyna Guzow ◽  
Anna Herman-Antosiewicz
Keyword(s):  
Cancer Cells ◽  
Tumour Growth ◽  
Current Knowledge ◽  
Biological Fluids ◽  
Parent Compound ◽  
Usnic Acid ◽  
Xenograft Model ◽  
Mechanisms Of Action ◽  
Cytotoxic Agents ◽  
Lead Compound

Abstract Purpose of Review This article summarises recent research on modifications of the structure or formula of usnic acid (UA), a lichen secondary metabolite, in order to obtain derivatives with higher bioavailability, potency and selectivity against cancer cells and presents the current knowledge on the mechanisms of action of such compounds. Recent Findings Numerous approaches have been undertaken to improve bioactivity of UA concerning its use as an anticancer drug. Among them, the synthesis of UA salts or complexation with 2-hydroxypropyl-β-cyclodextrin to improve its solubility and the encapsulation using different carriers (including various nanomaterials) to stabilise UA in biological fluids and improve their penetrance to, and release in, cancer cells were applied.. Synthetic modification of the UA structure has been explored to obtain more active and cancer-specific derivatives. Recent work indicates that some modifications of the C or A ring of UA selectively increase its antiproliferative potential against cancer cells. Moreover, specific changes in the UA structure allow to obtain derivatives which inhibit enzymes important for the cancer cells’ survival, such as mTOR, Pim, TDP1 or PARP. Some of them have been shown to enhance anticancer activity of the already approved chemotherapeutics, such as topotecan. Others, when used in an animal cancer xenograft model, were superior to UA in retardation of tumour growth and less toxic that the parent compound. Summary UA is a promising lead compound for synthesis of anticancer drugs. Further work on its modifications, mechanisms of activity and validation in animal models is critical for development of effective therapeutics.

Computational Approaches in Antibody-drug Conjugate Optimization for Targeted Cancer Therapy

2018 ◽  
Vol 18 (13) ◽  
pp. 1091-1109 ◽  
Author(s):  
Rita Melo ◽  
Agostinho Lemos ◽  
Antonio J. Preto ◽  
Jose G. Almeida ◽  
Joao D.G. Correia ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Coarse Grained ◽  
Cytotoxic Agent ◽  
Target Cells ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Cross Correlation Analysis ◽  
Traditional Therapies ◽  
Modular Structures ◽  
Antibody Drug

Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second- and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.

Synthesis and Evaluation of Aromatic Surfactants as Potential Antibacterial and Cytotoxic Agents

2019 ◽  
Vol 16 (6) ◽  
pp. 478-484
Author(s):  
Kenia Barrantes ◽  
Mary Fuentes ◽  
Luz Chacón ◽  
Rosario Achí ◽  
Jorge Granados-Zuñiga ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Hela Cells ◽  
Cytotoxic Agents ◽  
Cytotoxic Activities ◽  
Hydroxybenzoic Acid ◽  
Derivatives Of

Two ether and one ester derivatives of the 4-nitro-3-hydroxybenzoic acid were synthesized and characterized. The in vitro antimicrobial and cytotoxic activities of the three novel compounds were also evaluated. The aromatic derivatives showed antibacterial activity against one of the four microorganisms tested and two compounds (C8 and NOBA) had a lower IC50 in HeLa cells.

Synthesis and Biological Evaluation of Novel Osthol Derivatives as Potent Cytotoxic Agents

2019 ◽  
Vol 15 (2) ◽  
pp. 138-149
Author(s):  
Saleem Farooq ◽  
Javid A. Banday ◽  
Aashiq Hussain ◽  
Momina Nazir ◽  
Mushtaq A. Qurishi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Natural Product ◽  
Cancer Therapeutics ◽  
Inhibitory Effect ◽  
Biological Evaluation ◽  
Negative Control ◽  
Normal Breast ◽  
Cytotoxic Agents ◽  
Breast Epithelial Cell ◽  
Exciting Field

Background: Natural product, osthol has been found to have important biological and pharmacological roles particularly having inhibitory effect on multiple types of cancer. Objective: The unmet needs in cancer therapeutics make its derivatization an important and exciting field of research. Keeping this in view, a whole new series of diverse analogues of osthol (1) were synthesized. Method: All the newly synthesized compounds were made through modification in the lactone ring as well as in the side chain of the osthol molecule and were subjected to anti-proliferative screening through 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) against four different human cancers of diverse origins viz. Colon (Colo-205), lung (A549), Leukemia (THP- 1) and breast (MCF-7) including SV40 transformed normal breast epithelial cell (fR-2). Results: Interestingly, among the tested molecules, most of the analogs displayed better antiproliferative activity than the parent Osthol 1. However, among all the tested analogs, compound 28 exhibited the best results against leukemia (THP1) cell line with IC50 of 5µM.Compound 28 induced potent apoptotic effects and G1 phase arrest in leukemia cancer cells (THP1). The population of apoptotic cells increased from 13.8% in negative control to 26.9% at 8μM concentration of 28. Compound 28 also induced a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of the cancer cells. Conclusion: A novel series of molecules derived from natural product osthol were synthesized, wherein compound 28 was found to be most effective against leukemia and with 10 fold less toxicity against normal cells. The compound induced cancer inhibition mainly through apoptosis and thus has a potential in cancer therapeutics.

Theoretical Study of the Process of Passage of Glycoside Amides through the Cell Membrane of Cancer Cell

2020 ◽  
Vol 20 ◽  
Author(s):  
Vasil Tsanov ◽  
Hristo Tsanov
Keyword(s):  
Cell Membrane ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Quantum Chemical ◽  
Density Functional ◽  
Enzyme Regulation ◽  
Amide Derivatives ◽  
Pass Through ◽  
Hydrolysis Of ◽  
Derivatives Of

Background:: This article concentrates on the processes occurring in the medium around the cancer cell and the transfer of glycoside amides through their cell membrane. They are obtained by modification of natural glycoside-nitriles (cyano-glycosides). Hydrolysis of starting materials in the blood medium and associated volume around physiologically active healthy and cancer cells, based on quantum-chemical semi-empirical methods, is considered. Objective:: Based on the fact that the cancer cell feeds primarily on carbohydrates, it is likely that organisms have adapted to take food containing nitrile glycosides and / or modified forms to counteract "external" bioactive activity. Cancers, for their part, have evolved to create conditions around their cells that eliminate their active apoptotic forms. This is far more appropriate for them than changing their entire enzyme regulation to counteract it. In this way, it protects itself and the gene sets and develops according to its instructions. Methods:: Derived pedestal that closely defines the processes of hydrolysis in the blood, the transfer of a specific molecular hydrolytic form to the cancer cell membrane and with the help of time-dependent density-functional quantum- chemical methods, its passage and the processes of re-hydrolysis within the cell itself, to forms causing chemical apoptosis of the cell - independent of its non-genetic set, which seeks to counteract the process. Results:: Used in oncology it could turn a cancer from a lethal to a chronic disease (such as diabetes). The causative agent and conditions for the development of the disease are not eliminated, but the amount of cancer cells could be kept low for a long time (even a lifetime). Conclusion:: The amide derivatives of nitrile glycosides exhibit anti-cancer activity, the cancer cell probably seeks to displace hydrolysis of these derivatives in a direction that would not pass through its cell membrane and the amide- carboxyl derivatives of nitrile glycosides could deliver extremely toxic compounds within the cancer cell itself and thus block and / or permanently damage its normal physiology.

scholarly journals Cytotoxic Agents in the Minor Alkaloid Groups of the Amaryllidaceae

Planta Medica ◽  
2021 ◽  
Author(s):  
Jerald J. Nair ◽  
Johannes van Staden
Keyword(s):  
Cancer Cells ◽  
Cancer Cell Line ◽  
Structural Features ◽  
Biological Properties ◽  
Cytotoxic Agents ◽  
Plant Family ◽  
Structure Activity ◽  
Significant Interest ◽  
Different Types ◽  
Minor Alkaloid

AbstractOver 600 alkaloids have to date been identified in the plant family Amaryllidaceae. These have been arranged into as many as 15 different groups based on their characteristic structural features. The vast majority of studies on the biological properties of Amaryllidaceae alkaloids have probed their anticancer potential. While most efforts have focused on the major alkaloid groups, the volume and diversity afforded by the minor alkaloid groups have promoted their usefulness as targets for cancer cell line screening purposes. This survey is an in-depth review of such activities described for around 90 representatives from 10 minor alkaloid groups of the Amaryllidaceae. These have been evaluated against over 60 cell lines categorized into 18 different types of cancer. The montanine and cripowellin groups were identified as the most potent, with some in the latter demonstrating low nanomolar level antiproliferative activities. Despite their challenging molecular architectures, the minor alkaloid groups have allowed for facile adjustments to be made to their structures, thereby altering the size, geometry, and electronics of the targets available for structure-activity relationship studies. Nevertheless, it was seen with a regular frequency that the parent alkaloids were better cytotoxic agents than the corresponding semisynthetic derivatives. There has also been significant interest in how the minor alkaloid groups manifest their effects in cancer cells. Among the various targets and pathways in which they were seen to mediate, their ability to induce apoptosis in cancer cells is most appealing.

Cytotoxic agents and radiation therapy: mechanisms of action and clinical applications

2014 ◽  
Vol 14 (1) ◽  
pp. 63-69
Author(s):  
Amanda Marrone ◽  
William T. Tran
Keyword(s):  
Cell Cycle ◽  
Radiation Therapy ◽  
Disease Free Survival ◽  
Treatment Resistance ◽  
Mechanisms Of Action ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Theoretical Frameworks ◽  
Oncological Diseases ◽  
Health Database

AbstractBackgroundThe combination of radiation therapy and chemotherapy is rooted in its ability to help achieve locoregional and systemic control, therefore increasing the overall disease-free survival of patients. Understanding the mechanistic actions of cytotoxic agents and their targets on the cell cycle, as well as the governing pharmacokinetic principles can improve treatment delivery. The adjuvant treatment setting can overcome barriers such as hypoxia and genetically driven treatment resistance.PurposeThe purpose of this review is to present theoretical frameworks behind the chemoradiation paradigm and to describe current chemoradiation practices in radiation oncology.MethodologyA review was conducted using the US National Library of Medicine, National Institutes of Health database (PubMed) using the following search keywords: chemoradiation, spatial cooperation, chemotherapeutic agents, pharmacokinetics, anti-vascular agents, tumour vasculature and tumour hypoxia.Results and conclusionsCurrent research has reported several rationales for the beneficial combination of radiation and chemotherapy to eradicate oncological diseases. Mechanisms of action and biological approaches are showing that concurrent treatments, as well as novel agents such as anti-vascular and anti-angiogenic agents may benefit improved treatment outcomes by reducing micro hypoxic environments in tumours. In addition, chemotherapy administered in tandem with radiation enhances cell-killing effects by targeting the cell cycle.

scholarly journals Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

2014 ◽  
Vol 24 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Angeles Alvarez Secord ◽  
Deanna Teoh ◽  
Jingquan Jia ◽  
Andrew B. Nixon ◽  
Lisa Grace ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Combination Index ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Ovarian Cancer Cells ◽  
Response Curves ◽  
Pathway Activation ◽  
Skov3 Cells

PurposeThis study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.MethodsCells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.ResultsIn the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%–33%; P = 0.002 to 0.04) and p-paxicillin (6%–19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49–0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49–2.27).ConclusionsDasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

scholarly journals Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 386 ◽  
Author(s):  
Hiroshi Sugano ◽  
Yoshihiro Shirai ◽  
Takashi Horiuchi ◽  
Nobuhiro Saito ◽  
Yohta Shimada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Cytotoxic Agents ◽  
Migration And Invasion ◽  
Nafamostat Mesilate ◽  
Tumor Invasiveness ◽  
Radiation Induced ◽  
Induced Apoptosis

Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.

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