Hybrid Molecules with Potential Activity against Drug-resistant Cancer – PART-I

2021 ◽  
Vol 21 (19) ◽  
pp. 1711-1711
Author(s):  
Lian-Shun Feng
Keyword(s):  
Anticancer Agents ◽  
Intracellular Signaling ◽  
Hydroxamic Acid ◽  
Rational Design ◽  
Tumor Therapy ◽  
The Body ◽  
Drug Resistant ◽  
Hybrid Molecules

Cancer, which can invade almost all parts of the body, accounts for 18% of all deaths throughout the world and ranks as one of the leading causes of death among non-communicable diseases [1, 2]. Since cancers have a high chance of curing if appropriate treatment is provided, anticancer agents are critical for tumor therapy. However, the continuous emergency of drug-resistant cancer has already become one of the major challenges in the control and eradication of cancers [3, 4]. Therefore, dis-covering the next wave of anticancer agents with high potency against drug-resistant forms is vital. Coumarin, podophyllotoxin, hydroxamic acid, ferrocene, and acridine derivatives cannot only in-hibit tumor proliferation, invasion, and metastasis by acting on multiple intracellular signaling net-work molecules but also have reverse cancer multidrug resistance effect [5-9]. Moreover, many cur-rent available anticancer agents own these pharmacophores, demonstrating the potential of these pharmacophores to fight against various cancers, including drug-resistant forms. Hybridization repre-sents a promising strategy to develop novel anticancer agents since hybrid molecules can simultaneously act on dual or multi-ple cancer-relevant targets, such as metalloproteinases, ATP binding cassette subfamily G member 2 (ABCG2), human mito-chondrial peptide deformylase, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), P-glycoprotein (P-gp), tubulin, and vascular endothelial growth factor (VEGF) [10, 11]. Thus, hybrid molecules can increase specificity, reduce side effects, improve patient compliance, and overcome drug resistance [12]. Accordingly, a combination of coumarin, podophyl-lotoxin, hydroxamic acid, ferrocene, or acridine with other anticancer pharmacophores is an attractive strategy for the discov-ery of novel anticancer agents with potent activity against various cancers, especially drug-resistant forms. This special issue focuses on the current scenario of coumarin, podophyllotoxin, hydroxamic acid, ferrocene, and acridine hybrids with in vitro and in vivo anticancer potential. The mechanisms of action, the critical aspects of design, and structure-activity relationships are also discussed to pave the way for the further rational design of novel candidates with excellent effi-ciency against drug-resistant cancers.

Nanocurcumin: A Double-Edged Sword for Microcancers

2020 ◽  
Vol 26 (45) ◽  
pp. 5783-5792
Author(s):  
Kholood Abid Janjua ◽  
Adeeb Shehzad ◽  
Raheem Shahzad ◽  
Salman Ul Islam ◽  
Mazhar Ul Islam
Keyword(s):  
Intracellular Signaling ◽  
Dosage Forms ◽  
The Body ◽  
In Vivo Studies ◽  
Mrna Levels ◽  
Anticancer Activities ◽  
Road Map ◽  
Anticancer Effects

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

2019 ◽  
Vol 40 (3) ◽  
pp. 931-971 ◽  
Author(s):  
Lian‐Shun Feng ◽  
Zhi Xu ◽  
Le Chang ◽  
Chuan Li ◽  
Xiao‐Fei Yan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Drug Resistant ◽  
Hybrid Molecules

scholarly journals Toxic Effects of Metallopharmaceuticals

2017 ◽  
Vol 18 (3) ◽  
pp. 191-194 ◽  
Author(s):  
Slobodan Novokmet ◽  
Isidora Stojic ◽  
Katarina Radonjic ◽  
Maja Savic ◽  
Jovana Jeremic
Keyword(s):  
Metal Complexes ◽  
Transition Metal Complexes ◽  
Anticancer Agents ◽  
Rational Design ◽  
Current Knowledge ◽  
The Past ◽  
Ru Complexes ◽  
Key Features

Abstract Discovery of the metallopharmaceutical cisplatin and its use in antitumour therapy has initiated the rational design and screening of metal-based anticancer agents as potential chemotherapeutics. In addition to the achievements of cisplatin and its therapeutic analogues, there are significant drawbacks to its use: resistance and toxicity. Over the past four decades, numerous transition metal complexes have been synthesized and investigated in vitro and in vivo. The most studied metals among these complexes are platinum and ruthenium. The key features of these investigations is to find novel metal complexes that could potentially exert less toxicity and equal or higher antitumour potency and to overcome other pharmacological deficiencies. Ru complexes have a different mode of action than cisplatin does, some of which are under clinical trials for treating metastatic or cisplatin-resistant tumours. This review consists of the current knowledge, published and unpublished, related to the toxicity of metallopharmaceuticals, and special attention is given to platinum [Pt(II) and Pt(IV)] and ruthenium [Ru(II) and Ru(III)] complexes.

scholarly journals Repurposing Tranexamic Acid as an Anticancer Agent

2021 ◽  
Author(s):  
Mary E Law ◽  
Bradley J Davis ◽  
Amanda F Ghilardi ◽  
Elham Yaaghubi ◽  
Zaafir M Dulloo ◽  
...  
Keyword(s):  
Tranexamic Acid ◽  
Anticancer Agents ◽  
Intracellular Signaling ◽  
Anticancer Agent ◽  
Lead Compounds ◽  
Intracellular Signaling Pathways ◽  
Multiple Processes ◽  
Broad Array

Tranexamic Acid (TA) is a clinically used antifibrinolytic that acts as a lysine mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic lysine and arginine, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

scholarly journals Losing the Battle but Winning the War: Can Defeated Antibacterials Form Alliances to Combat Drug-Resistant Pathogens?

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 646
Author(s):  
Song Oh ◽  
Raymond Chau ◽  
Anh T. Nguyen ◽  
Justin R. Lenhard
Keyword(s):  
Clinical Studies ◽  
Rational Design ◽  
Multidrug Resistant ◽  
Optimal Combination ◽  
In Vivo Studies ◽  
Drug Resistant ◽  
Current Review ◽  
Antimicrobial Combinations

Despite the recent development of antibacterials that are active against multidrug-resistant pathogens, drug combinations are often necessary to optimize the killing of difficult-to-treat organisms. Antimicrobial combinations typically are composed of multiple agents that are active against the target organism; however, many studies have investigated the potential utility of combinations that consist of one or more antibacterials that individually are incapable of killing the relevant pathogen. The current review summarizes in vitro, in vivo, and clinical studies that evaluate combinations that include at least one drug that is not active individually against Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, or Staphylococcus aureus. Polymyxins were often included in combinations against all three of the Gram-negative pathogens, and carbapenems were commonly incorporated into combinations against K. pneumoniae and A. baumannii. Minocycline, sulbactam, and rifampin were also frequently investigated in combinations against A. baumannii, whereas the addition of ceftaroline or another β-lactam to vancomycin or daptomycin showed promise against S. aureus with reduced susceptibility to vancomycin or daptomycin. Although additional clinical studies are needed to define the optimal combination against specific drug-resistant pathogens, the large amount of in vitro and in vivo studies available in the literature may provide some guidance on the rational design of antibacterial combinations.

Nanosponges Encapsulated Phytochemicals for Targeting Cancer: A Review

2020 ◽  
Vol 21 ◽  
Author(s):  
Shailaja Dombe ◽  
Pramodkumar Shirote
Keyword(s):  
Drug Delivery ◽  
Anticancer Agents ◽  
Biological Properties ◽  
The Body ◽  
Special Focus ◽  
Cancer Therapies ◽  
Nanostructured Particles ◽  
Inorganic Systems

Abstract: Cancer is the most ruinous disease globally. Natural products have impressive characteristics, such as excep-tional chemical versatility, chemical and biological properties of macromolecular specificity and less toxicity which make them good leads in finding novel drugs. The phytochemicals not only help to prevent but also treat chronic cancerous conditions. The present review attempts to put forth some selected anticancer phytochemicals that had reported omics char-acteristic and specifically suppressed cancer with in vitro and in vivo activity. Certain issues pertaining to anticancer phy-tochemicals like delivery to target site in the body and achieving controlled release in order to prevent overdoses havelong been a concern for medical researchers worldwide. The most conventional chemotherapy protocols for the treatment of cancer lead to adverse effects that limit biological efficacy and compromise patient outcomes. In order to defeat incompe-tency of current and upcoming natural anticancer agents and to attain targeted drug delivery with good efficacy and fewer side effects, there is a special focus on novel nanostructured particles and nano approaches consisting of carrier system. Recent studies have led to the discovery of mesoporous and nanoporous drug delivery mechanisms, such as inorganic or organic-based nanosponges. The metal based inorganic systems have exhibited toxicity and non-biodegradable character in vivo. As a result of problems related to inorganic systems, major shift of research from inorganic to organic nanosystems has occurred. About decades ago, researchers have developed organic nanosponges to control the limitation of drug delivery and cancer therapies. This review article discusses the development and application of nanosponges encapsulated phyto-chemicals for cancer therapy.

scholarly journals Repurposing Tranexamic Acid as an Anticancer Agent

2022 ◽  
Vol 12 ◽  
Author(s):  
Mary E. Law ◽  
Bradley J. Davis ◽  
Amanda F. Ghilardi ◽  
Elham Yaaghubi ◽  
Zaafir M. Dulloo ◽  
...  
Keyword(s):  
Tranexamic Acid ◽  
Anticancer Agents ◽  
Intracellular Signaling ◽  
Anticancer Agent ◽  
Lead Compounds ◽  
Intracellular Signaling Pathways ◽  
Multiple Processes ◽  
Broad Array

Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

1,3,5-Triazine-azole Hybrids and their Anticancer Activity

2020 ◽  
Vol 20 (16) ◽  
pp. 1481-1492
Author(s):  
Hua Guo ◽  
Quan-Ping Diao
Keyword(s):  
Clinical Trials ◽  
Anticancer Activity ◽  
Anticancer Agents ◽  
Mechanisms Of Action ◽  
Structure Activity ◽  
Hybrid Molecules ◽  
Excellent Activity ◽  
Enhance Efficiency

1,3,5-Triazine and azole can interact with various therapeutic targets, and their derivatives possess promising in vitro and in vivo anticancer activity. Hybrid molecules have the potential to enhance efficiency, overcome drug resistance and reduce side effects, and many hybrid molecules are under different phases of clinical trials, so hybridization of 1,3,5-triazine with azole may provide valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop azole-containing 1,3,5-triazine hybrids as novel anticancer agents, and some of them exhibited excellent activity. This review emphasizes azole-containing 1,3,5-triazine hybrids with potential anticancer activity, and the structure-activity relationships as well as the mechanisms of action are also discussed to provide comprehensive and target-oriented information for the development of this kind of anticancer drugs.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Репрограммированые in vitro на М3 фенотип макрофаги останавливают рост солидной карциномы in vivo

2018 ◽  
pp. 41-46
Author(s):  
А.А. Раецкая ◽  
С.В. Калиш ◽  
С.В. Лямина ◽  
Е.В. Малышева ◽  
О.П. Буданова ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Antitumor Effect ◽  
Tumor Development ◽  
Significant Inhibition ◽  
The Body ◽  
Ehrlich Carcinoma ◽  
Solid Carcinoma ◽  
Ec Cells

Цель исследования. Доказательство гипотезы, что репрограммированные in vitro на М3 фенотип макрофаги при введении в организм будут существенно ограничивать развитие солидной карциномы in vivo . Методика. Рост солидной опухоли инициировали у мышей in vivo путем подкожной инъекции клеток карциномы Эрлиха (КЭ). Инъекцию макрофагов с нативным М0 фенотипом и с репрограммированным M3 фенотипом проводили в область формирования солидной КЭ. Репрограммирование проводили с помощью низких доз сыворотки, блокаторов факторов транскрипции STAT3/6 и SMAD3 и липополисахарида. Использовали две схемы введения макрофагов: раннее и позднее. При раннем введении макрофаги вводили на 1-е, 5-е, 10-е и 15-е сут. после инъекции клеток КЭ путем обкалывания макрофагами с четырех сторон область развития опухоли. При позднем введении, макрофаги вводили на 10-е, 15-е, 20-е и 25-е сут. Через 15 и 30 сут. после введения клеток КЭ солидную опухоль иссекали и измеряли ее объем. Эффект введения макрофагов оценивали качественно по визуальной и пальпаторной характеристикам солидной опухоли и количественно по изменению ее объема по сравнению с группой без введения макрофагов (контроль). Результаты. Установлено, что M3 макрофаги при раннем введении от начала развития опухоли оказывают выраженный антиопухолевый эффект in vivo , который был существенно более выражен, чем при позднем введении макрофагов. Заключение. Установлено, что введение репрограммированных макрофагов M3 ограничивает развитие солидной карциномы в экспериментах in vivo . Противоопухолевый эффект более выражен при раннем введении М3 макрофагов. Обнаруженные в работе факты делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли, путем предварительного программирования антиопухолевого врожденного иммунного ответа «в пробирке». Aim. To verify a hypothesis that macrophages reprogrammed in vitro to the M3 phenotype and injected into the body substantially restrict the development of solid carcinoma in vivo . Methods. Growth of a solid tumor was initiated in mice in vivo with a subcutaneous injection of Ehrlich carcinoma (EC) cells. Macrophages with a native M0 phenotype or reprogrammed towards the M3 phenotype were injected into the region of developing solid EC. Reprogramming was performed using low doses of serum, STAT3/6 and SMAD3 transcription factor blockers, and lipopolysaccharide. Two schemes of macrophage administration were used: early and late. With the early administration, macrophages were injected on days 1, 5, 10, and 15 following the injection of EC cells at four sides of the tumor development area. With the late administration, macrophages were injected on days 10, 15, 20, and 25. At 15 and 30 days after the EC cell injection, the solid tumor was excised and its volume was measured. The effect of macrophage administration was assessed both qualitatively by visual and palpation characteristics of solid tumor and quantitatively by changes in the tumor volume compared with the group without the macrophage treatment. Results. M3 macrophages administered early after the onset of tumor development exerted a pronounced antitumor effect in vivo , which was significantly greater than the antitumor effect of the late administration of M3 macrophages. Conclusion. The observed significant inhibition of in vivo growth of solid carcinoma by M3 macrophages makes promising the development of a clinical version of the biotechnology for restriction of tumor growth by in vitro pre-programming of the antitumor, innate immune response.

Sign in / Sign up

Export Citation Format

Share Document