The Promise of Integrins as Effective Targets for Anticancer Agents

This review will briefly describe integrin function, address why integrins are attractive targets for chemotherapeutic drug design, and discuss some ongoing studies aimed at inhibiting integrin activity. Integrins are cell surface heterodimeric receptors. They modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Many potential chemotherapeutic agents target integrins directly (eg, polypeptides, monoclonal antibodies, adenovirus vectors). These agents may be clinically useful in controlling the metastatic spread of cancer.

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Cancer Therapy–Associated Thrombosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314378 ◽

2021 ◽

Vol 41 (4) ◽

pp. 1291-1305

Author(s):

Steven P. Grover ◽

Yohei M. Hisada ◽

Raj S. Kasthuri ◽

Brandi N. Reeves ◽

Nigel Mackman

Keyword(s):

Venous Thrombosis ◽

Anticancer Agents ◽

Treatment Strategies ◽

Chemotherapeutic Agents ◽

Malignant Cells ◽

Related Factors ◽

Cellular Processes ◽

Patients With Cancer ◽

Increased Risk ◽

Direct Cytotoxicity

Patients with cancer have an increased risk of both arterial and venous thrombotic events compared with the general population. Both the site and stage of cancer are known to contribute to the increased risk of thrombotic events. In addition, several treatment-related factors enhance the risk of thrombosis, including hospitalization, surgery, central venous catheters, radiation, and anticancer agents. Chemotherapy serves as a mainstay treatment for a broad range of malignancies. Chemotherapeutic agents typically exert antineoplastic effects through either direct cytotoxicity or inhibition of cellular processes necessary for the proliferation of malignant cells. Unfortunately, in addition to targeting malignant cells, chemotherapeutic agents are also cytotoxic to nonmalignant cells. Chemotherapeutic agents have been associated with an increased risk of arterial and venous thrombosis. More recently, targeted agents have been developed that offer improved selectivity towards malignant cells. However, some of these agents are also associated with an increased risk of both arterial and venous thrombosis. Here, we review the association between specific anticancer agents and thrombotic events in patients with cancer. Despite an established association in most cases, the mechanism by which these agents increase thrombosis is poorly understood. Anticancer agents may damage the endothelium, decrease anticoagulants or increase procoagulants leading to activation of coagulation, or activate platelets. An improved understanding of the mechanisms that drive the increased risk of thrombotic events associated with anticancer agents will enable treatment strategies that mitigate this risk.

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Novel Chemotherapeutic Agents - The Contribution of Scorpionates

Current Medicinal Chemistry ◽

10.2174/0929867325666180914104237 ◽

2020 ◽

Vol 26 (41) ◽

pp. 7452-7475 ◽

Cited By ~ 1

Author(s):

Marta A. Andrade ◽

Luísa M.D.R.S. Martins

Keyword(s):

Transition Metal ◽

Metal Complexes ◽

Transition Metal Complexes ◽

Anticancer Agents ◽

Medicinal Chemistry ◽

Bioinorganic Chemistry ◽

Chemotherapeutic Agents ◽

Great Role ◽

Anticancer Properties ◽

Scorpionate Ligands

: The development of safe and effective chemotherapeutic agents is one of the uppermost priorities and challenges of medicinal chemistry and new transition metal complexes are being continuously designed and tested as anticancer agents. Scorpionate ligands have played a great role in coordination chemistry, since their discovery by Trofimenko in the late 1960s, with significant contributions in the fields of catalysis and bioinorganic chemistry. Scorpionate metal complexes have also shown interesting anticancer properties, and herein, the most recent (last decade) and relevant scorpionate complexes reported for application in medicinal chemistry as chemotherapeutic agents are reviewed. The current progress on the anticancer properties of transition metal complexes bearing homo- or hetero- scorpionate ligands, derived from bis- or tris-(pyrazol-1-yl)-borate or -methane moieties is highlighted.

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Cytoprotective Agents to Avoid Chemotherapy Induced Sideeffects on Normal Cells: A Review

Current Cancer Drug Targets ◽

10.2174/1568009619666190326120457 ◽

2019 ◽

Vol 19 (10) ◽

pp. 765-781

Author(s):

Seema Rohilla ◽

Harish Dureja ◽

Vinay Chawla

Keyword(s):

Adverse Effects ◽

Anticancer Agents ◽

Therapeutic Index ◽

Chemotherapeutic Agents ◽

Vital Role ◽

Normal Cells ◽

Normal Tissues ◽

Organ Specific ◽

Delay In Treatment

Anticancer agents play a vital role in the cure of patients suffering from malignancy. Though, the chemotherapeutic agents are associated with various adverse effects which produce significant toxic symptoms in the patients. But this therapy affects both the malignant and normal cells and leads to constricted therapeutic index of antimalignant drugs which adversely impacts the quality of patients’ life. Due to these adversities, sufficient dose of drug is not delivered to patients leading to delay in treatment or improper treatment. Chemoprotective agents have been developed either to minimize or to mitigate the toxicity allied with chemotherapeutic agents. Without any concession in the therapeutic efficacy of anticancer drugs, they provide organ specific guard to normal tissues.

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Synthesis and Biological Evaluations of Organoruthenium Scaffolds: A Comprehensive Update

Current Organic Synthesis ◽

10.2174/1570179414666170703143049 ◽

2018 ◽

Vol 15 (2) ◽

pp. 179-207

Author(s):

Ashaparna Mondal ◽

Priyankar Paira

Keyword(s):

Singlet Oxygen ◽

Anticancer Agents ◽

Ruthenium Complexes ◽

Chemotherapeutic Agents ◽

Quantum Yields ◽

Ros Generation ◽

Standard Drug ◽

Cellular Environment ◽

Theranostic Agents

Background: Currently ruthenium complexes are immerging as effective anticancer agents due to their less toxicity, better antiproliferative and antimetastatic activity, better stability in cellular environment and most importantly variable oxidation and co-ordination states of ruthenium allows binding this molecule with a variety of ligands. So in past few years researchers have shifted their interest towards organoruthenium complexes having good fluorescent profile that may be applicable for cancer theranostics. Nowadays, photodynamic therapy has become more acceptable because of its easy and effective approach towards killing cancer cells. Objective: Objective of this review article is to shed light on synthesis, characterization, stability and fluorescence studies of various ruthenium [Ru(II) and Ru(III)] complexes and different bioactivity studies conducted with the synthesized compounds to test their candidacy as potent chemotherapeutic agents. Methods: Various heterocyclic ligands containing N,O and S as heteroatom mainly were prepared and subjected to complexation with ruthenium-p-cymene moiety. In most cases [Ru(η6-p-cymene)(µ-Cl)Cl]2 was used as ruthenium precursor and the reactions were conducted in various alcohol medium such as methanol, ethanol or propanol. The synthesized complexes were characterized by 1H NMR and 13C NMR spectroscopy, GC-MS, ESI-MS, elemental analysis and single crystal X-ray crystallography methods. Fluorescence study and stability study were conducted accordingly using water, PBS buffer or DMSO. Stable compounds were considered for cell viability studies. To study the efficacy of the compounds in ROS generation as photosensitizers, in few cases, singlet oxygen quantum yields in presence of light were calculated. Suitable compounds were selected for in vitro & in vivo antiproliferative, anti-invasive activity studies. Result: Many newly synthesized compounds were found to have less IC50 compared to a standard drug cysplatin. Those compounds were also stable preferably in physiological conditions. Good fluorescence profile and ROS generation ability were observed for few compounds. Conclusion: Numerous ruthenium complexes were developed which can be used as cancer theranostic agents. Few molecules were synthesized as photosensitizers which were supposed to generate reactive singlet oxygen species in targeted cellular environment in presence of a particular type of light and thereby ceasing cancer cell growth.

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Zoning in on Tankyrases: A Brief Review on the Past, Present and Prospective Studies

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666191019114321 ◽

2020 ◽

Vol 19 (16) ◽

pp. 1920-1934

Author(s):

Xylia Q. Peters ◽

Thembeka H. Malinga ◽

Clement Agoni ◽

Fisayo A. Olotu ◽

Mahmoud E.S. Soliman

Keyword(s):

Drug Design ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Design Methods ◽

Selective Inhibitors ◽

Computer Aided Drug Design ◽

Cellular Processes ◽

Conventional Drug ◽

Computer Aided ◽

Tankyrase 1

Background: Tankyrases are known for their multifunctionalities within the poly(ADPribose) polymerases family and playing vital roles in various cellular processes which include the regulation of tumour suppressors. Tankyrases, which exist in two isoforms; Tankyrase 1 and 2, are highly homologous and an integral part of the Wnt β -catenin pathway that becomes overly dysregulated when hijacked by pro-carcinogenic machineries. Methods: In this review, we cover the distinct roles of the Tankyrase isoforms and their involvement in the disease pathogenesis. Also, we provide updates on experimentally and computationally derived antagonists of Tankyrase whilst highlighting the precedence of integrative computer-aided drug design methods towards the discovery of selective inhibitors. Results: Despite the high prospects embedded in the therapeutic targeting and blockade of Tankyrase isoforms, the inability of small molecule inhibitors to achieve selective targeting has remained a major setback, even until date. This explains numerous incessant drug design efforts geared towards the development of highly selective inhibitors of the respective Tankyrase isoforms since they mediate distinct aberrancies in disease progression. Therefore, considering the setbacks of conventional drug design methods, can computer-aided approaches actually save the day? Conclusion: The implementation of computer-aided drug design techniques in Tankyrase research could help complement experimental methods and facilitate ligand/structure-based design and discovery of small molecule inhibitors with enhanced selectivity.

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Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽

10.3390/cells8091037 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1037 ◽

Cited By ~ 6

Author(s):

Cho ◽

Kim ◽

Baek ◽

Kim ◽

Lee

Keyword(s):

Cell Migration ◽

Cancer Progression ◽

Anticancer Agents ◽

Rho Gtpases ◽

Rho Gtpase ◽

Regulatory Mechanisms ◽

Malignant Phenotype ◽

Cellular Processes ◽

Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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Naphthalimide-Containing BP100 Leads to Higher Model Membranes Interactions and Antimicrobial Activity

Biomolecules ◽

10.3390/biom11040542 ◽

2021 ◽

Vol 11 (4) ◽

pp. 542

Author(s):

Gustavo Penteado Battesini Carretero ◽

Greice Kelle Viegas Saraiva ◽

Magali Aparecida Rodrigues ◽

Sumika Kiyota ◽

Marcelo Porto Bemquerer ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Biological Effects ◽

Membrane Surface ◽

Helical Structure ◽

Helical Conformation ◽

Property A ◽

Cellular Processes ◽

Double Stranded Dna ◽

Low Toxicity

In a large variety of organisms, antimicrobial peptides (AMPs) are primary defenses against pathogens. BP100 (KKLFKKILKYL-NH2), a short, synthetic, cationic AMP, is active against bacteria and displays low toxicity towards eukaryotic cells. BP100 acquires a α-helical conformation upon interaction with membranes and increases membrane permeability. Despite the volume of information available, the action mechanism of BP100, the selectivity of its biological effects, and possible applications are far from consensual. Our group synthesized a fluorescent BP100 analogue containing naphthalimide linked to its N-terminal end, NAPHT-BP100 (Naphthalimide-AAKKLFKKILKYL-NH2). The fluorescence properties of naphthalimides, especially their spectral sensitivity to microenvironment changes, are well established, and their biological activities against transformed cells and bacteria are known. Naphthalimide derived compounds are known to interact with DNA disturbing related processes as replication and transcription, and used as anticancer agents due to this property. A wide variety of techniques were used to demonstrate that NAPHT-BP100 bound to and permeabilized zwitterionic POPC and negatively charged POPC:POPG liposomes and, upon interaction, acquired a α-helical structure. Membrane surface high peptide/lipid ratios triggered complete permeabilization of the liposomes in a detergent-like manner. Membrane disruption was driven by charge neutralization, lipid aggregation, and bilayer destabilization. NAPHT-BP100 also interacted with double-stranded DNA, indicating that this peptide could also affect other cellular processes besides causing membrane destabilization. NAPHT-BP100 showed increased antibacterial and hemolytic activities, compared to BP100, and may constitute an efficient antimicrobial agent for dermatological use. By conjugating BP100 and naphthalimide DNA binding properties, NAPHT-BP100 bound to a large extent to the bacterial membrane and could more efficiently destabilize it. We also speculate that peptide could enter the bacteria cell and interact with its DNA in the cytoplasm.

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Fibrosis after Myocardial Infarction: An Overview on Cellular Processes, Molecular Pathways, Clinical Evaluation and Prognostic Value

Medical Sciences ◽

10.3390/medsci9010016 ◽

2021 ◽

Vol 9 (1) ◽

pp. 16

Author(s):

Renato Francesco Maria Scalise ◽

Rosalba De Sarro ◽

Alessandro Caracciolo ◽

Rita Lauro ◽

Francesco Squadrito ◽

...

Keyword(s):

Myocardial Infarction ◽

Signaling Pathways ◽

Ventricular Dysfunction ◽

Healing Process ◽

Molecular Signaling ◽

Cellular Processes ◽

Molecular Signaling Pathways ◽

Fibrotic Scar ◽

Life Threatening

The ischemic injury caused by myocardial infarction activates a complex healing process wherein a powerful inflammatory response and a reparative phase follow and balance each other. An intricate network of mediators finely orchestrate a large variety of cellular subtypes throughout molecular signaling pathways that determine the intensity and duration of each phase. At the end of this process, the necrotic tissue is replaced with a fibrotic scar whose quality strictly depends on the delicate balance resulting from the interaction between multiple actors involved in fibrogenesis. An inflammatory or reparative dysregulation, both in term of excess and deficiency, may cause ventricular dysfunction and life-threatening arrhythmias that heavily affect clinical outcome. This review discusses cellular process and molecular signaling pathways that determine fibrosis and the imaging technique that can characterize the clinical impact of this process in-vivo.

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Synthesis and characterization of a new series of thiadiazole derivatives as potential anticancer agents

Heterocyclic Communications ◽

10.1515/hc-2020-0002 ◽

2020 ◽

Vol 26 (1) ◽

pp. 6-13 ◽

Cited By ~ 1

Author(s):

Ulviye Acar Çevik ◽

Derya Osmaniye ◽

Serkan Levent ◽

Begüm Nurpelin Sağlik ◽

Betül Kaya Çavuşoğlu ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Cancer Cell Line ◽

Chemotherapeutic Agents ◽

Anticancer Activities ◽

Normal Tissues ◽

H Nmr ◽

Wide Range ◽

Thiadiazole Derivatives ◽

Low Efficiency

AbstractCancer is one of the most common causes of death in the world. Despite the importance of combating cancer in healthcare systems and research centers, toxicity in normal tissues and the low efficiency of anticancer drugs are major problems in chemotherapy. Nowadays the aim of many medical research projects is to discover new safer and more effective anticancer agents. 1,3,4-Thiadiazole compounds are important fragments in medicinal chemistry because of their wide range of biological activities, including anticancer activities. The aim of this study was to determine the capacity of newly synthesized 1,3,4-thiadiazole compounds as chemotherapeutic agents. The structures of the obtained compounds were elucidated using 1H-NMR, 13C-NMR and mass spectrometry. Although the thiadiazole derivatives did not prove to be significantly cytotoxic to the tumour tissue cultures, compound 4i showed activity against the C6 rat brain cancer cell line (IC50 0.097 mM) at the tested concentrations.

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Homeobox-A13 acts as a functional prognostic and diagnostic biomarker via regulating P53 and Wnt signaling pathways in lung cancer

Cancer Biomarkers ◽

10.3233/cbm-200540 ◽

2021 ◽

pp. 1-16

Author(s):

Yang Wang ◽

Bo He ◽

Yan Dong ◽

Gong-Jin He ◽

Xiao-Wei Qi ◽

...

Keyword(s):

Lung Cancer ◽

Signaling Pathways ◽

Cox Regression ◽

Prognostic Significance ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Clinical Feature ◽

Diagnostic Biomarker

BACKGROUND: The prognosis of lung cancer patients is poor without useful prognostic and diagnostic biomarker. To search for novel prognostic and diagnostic markers, we previously found homeobox-A13 (HOXA13) as a promising candidate in lung cancer. OBJECTIVE: To determine the precisely clinical feature, prognostic and diagnostic value, possible role and mechanism of HOXA13. METHODS: Gene-expression was explored by real-time quantitative-PCR, western-blot and tissue-microarray. The associations were analyzed by Chi-square test, Kaplan-Meier and Cox-regression. The roles and mechanisms were evaluated by MTS, EdU, transwell, xenograft tumor and luciferase-reporter assays. RESULTS: HOXA13 expression is increased in tumors, and correlated with age of patients. HOXA13 expression is associated with unfavorable overall survival and relapse-free survival of patients in four cohorts. Interestingly, HOXA13 has different prognostic significance in adenocarcinoma (ADC) and squamous-cell carcinoma (SCC), and is a sex- and smoke-related prognostic factor only in ADC. Importantly, HOXA13 can serve as a diagnostic biomarker for lung cancer, especially for SCC. HOXA13 can promote cancer-cell proliferation, migration and invasion in vitro, and facilitate tumorigenicity and tumor metastasis in vivo. HOXA13 acts the oncogenic roles on tumor growth and metastasis by regulating P53 and Wnt/β-catenin signaling activities in lung cancer. CONCLUSIONS: HOXA13 is a new prognostic and diagnostic biomarker associated with P53 and Wnt/β-catenin signaling pathways.

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