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.

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 Caffeine Inhibits EGF-Stimulated Trophoblast Cell Motility through the Inhibition of mTORC2 and Akt

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4502-4510 ◽  
Author(s):  
Isobelle Grant ◽  
Judith E. Cartwright ◽  
Brooke Lumicisi ◽  
Alison E. Wallace ◽  
Guy S. Whitley
Keyword(s):  
Cell Motility ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Pregnancy Loss ◽  
Mammalian Target Of Rapamycin ◽  
First Trimester ◽  
Trophoblast Invasion ◽  
Intracellular Signaling Pathways

Impaired trophoblast invasion is associated with pregnancy disorders such as early pregnancy loss and preeclampsia. There is evidence to suggest that the consumption of caffeine during pregnancy may increase the risk of pregnancy loss; however, little is known about the direct effect of caffeine on normal trophoblast biology. Our objectives were to examine the effect of caffeine on trophoblast migration and motility after stimulation with epidermal growth factor (EGF) and to investigate the intracellular signaling pathways involved in this process. Primary first-trimester extravillous trophoblasts (EVT) and the EVT-derived cell line SGHPL-4 were used to study the effect of caffeine on EGF-stimulated cellular motility using time-lapse microscopy. SGHPL-4 cells were further used to study the effect of caffeine and cAMP on EGF-stimulated invasion of fibrin gels. The influence of caffeine and cAMP on EGF-stimulated intracellular signaling pathways leading to the activation of Akt were investigated by Western blot analysis. Caffeine inhibits both EGF-stimulated primary EVT and SGHPL-4 cell motility. EGF stimulation activates phosphatidylinositol 3-kinase, and Akt and caffeine inhibit this activation. Although cAMP inhibits both motility and invasion, it does not inhibit the activation of Akt, indicating that the effects of caffeine seen in this study are independent of cAMP. Further investigation indicated a role for mammalian target of rapamycin complex 2 (mTORC2) as a target for the inhibitory effect of caffeine. In conclusion, we demonstrate that caffeine inhibits EGF-stimulated trophoblast invasion and motility in vitro and so could adversely influence trophoblast biology in vivo.

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.

Enhanced expression of proapoptotic and autophagic proteins involved in the cell death of glioblastoma induced by synthetic glycans

2014 ◽  
Vol 120 (6) ◽  
pp. 1298-1308 ◽  
Author(s):  
Ahmad Faried ◽  
Muhammad Zafrullah Arifin ◽  
Shogo Ishiuchi ◽  
Hiroyuki Kuwano ◽  
Shin Yazawa
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Anticancer Agents ◽  
Anticancer Agent ◽  
Adenosine Diphosphate ◽  
Glioblastoma Cells ◽  
Enhanced Expression ◽  
Autophagic Proteins

Object Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo. Methods The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans. Results Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans. Conclusions These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

scholarly journals Study of intracellular signaling pathways in Chronic Myeloproliferative Neoplasms

2018 ◽  
Author(s):  
Serena Martinelli
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Myeloproliferative Neoplasms ◽  
Mtor Pathway ◽  
Janus Kinase ◽  
Pi3k Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Intracellular Signaling Pathways

A gain-of-function mutation in Janus kinase 2 (JAK2V617F) is at the basis of the majority of chronic myeloproliferative neoplasms (MPN). Enhanced activation of other downstream pathways including the PI3K/mTOR pathway has been documented as well. In this study we evaluated the effects of JAK1/2 inhibitors, alone and in combination with mTOR, with a dual mTOR/PI3K inhibitor and with a pan PI3K inhibitor in in-vitro and in-vivo MPN models. Our findings of strong synergy between the JAK2 inhibitors and mTOR/PI3K inhibitor suggested that we might be able to administer these drugs at lower concentrations than when the drugs are used individually. This provides a framework for combination trials using compounds in patients with myeloproliferative neoplasms

Vitamin D as potential therapeutic anticancer agent

2018 ◽  
pp. 1-3
Keyword(s):  
Vitamin D ◽  
Anticancer Activity ◽  
Anticancer Agent ◽  
Antitumor Agents ◽  
Metastatic Potential ◽  
Anticancer Properties ◽  
Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

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.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

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