A Comprehensive Overview of the Developments of Cdc25 Phosphatase Inhibitors.

Cdc25 phosphatases have been considered promising targets for anticancer development due to the correlation of their overexpression with a wide variety of cancers. In the last two decades, the interest in this subject has considerably increased and many publications have been launched concerning this issue. An overview is constructed based on data analysis of the results of the previous publications covering the years from 1992 to 2021.

Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases.

The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.

Screening of indeno[1,2-b]indoloquinones by MALDI-MS: a new set of potential CDC25 phosphatase inhibitors brought to light.

Quinones and quinones-like compounds are potential candidates for the inhibition of CDC25 phosphatases. The combination of MALDI-MS analyses and biological studies was used to develop a rapid screening of a targeted library of indeno[1,2-b]indoloquinone derivatives. The screening protocol using MALDI-TOFMS and MALDI-FTICRMS highlighted four new promising candidates.

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites.

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes.

Plumbagin modulates leukemia cell redox status.

Plumbagin is a plant naphtoquinone exerting anti-cancer properties including apoptotic cell death induction and generation of reactive oxygen species (ROS). The aim of this study was to elucidate parameters explaining the differential leukemia cell sensitivity towards this compound. Among several leukemia cell lines, U937 monocytic leukemia cells appeared more sensitive to plumbagin treatment in terms of cytotoxicity and level of apoptotic cell death compared to more resistant Raji Burkitt lymphoma cells.

A novel coumarin-quinone derivative SV37 inhibits CDC25 phosphatases, impairs proliferation, and induces cell death.

Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach.

Genotoxic stress modulates CDC25C phosphatase alternative splicing in human breast cancer cell lines.

CDC25 (cell division cycle 25) phosphatases are essential for cell cycle control under normal conditions and in response to DNA damage. They are represented by three isoforms, CDC25A, B and C, each of them being submitted to an alternative splicing mechanism. Alternative splicing of many genes is affected in response to genotoxic stress, but the impact of such a stress on CDC25 splicing has never been investigated.

Aurones: interesting natural and synthetic compounds with emerging biological potential.

Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential.

Protection of CDC25 phosphatases against oxidative stress in breast cancer cells: evaluation of the implication of the thioredoxin system.

Reactive oxygen species regulate protein functionality. Cell cycle CDC25 phosphatases are targets of such oxidative regulation in vitro. We sought to evaluate if a thioredoxin (trx)-dependent redox regulation of CDC25 exists in cancer cells.

Coumarin polysulfides inhibit cell growth and induce apoptosis in HCT116 colon cancer cells.

Coumarins and coumarin derivatives as well as diallyl polysulfides are well known as anticancer drugs. In order to find new drugs with anticancer activities, we combined coumarins with polysulfides in the form of di-coumarin polysulfides. These novel compounds were tested in the HCT116 colorectal cancer cell line.

Control of oxidative posttranslational cysteine modifications: from intricate chemistry to widespread biological and medical applications.

Cysteine residues in proteins and enzymes often fulfill rather important roles, particularly in the context of cellular signaling, protein-protein interactions, substrate and metal binding, and catalysis. At the same time, some of the most active cysteine residues are also quite sensitive toward (oxidative) modification. S-Thiolation, S-nitrosation, and disulfide bond and sulfenic acid formation are processes which occur frequently inside the cell and regulate the function and activity of many proteins and enzymes.

Differential expression of CDC25 phosphatases splice variants in human breast cancer cells.

Background: CDC25 phosphatases control cell cycle progression by activating cyclin dependent kinases. The three CDC25 isoforms encoding genes are submitted to alternative splicing events which generate at least two variants for CDC25A and five for both CDC25B and CDC25C. An over-expression of CDC25 was reported in several types of cancer, including breast cancer, and is often associated with a poor prognosis.

Functional genomics towards personalized healthcare and systems medicine.

The 5th Biologie Prospective Santorini Conference explored the themes of systems biology, nutrigenomics and pharmacogenomics, all of which are related to personalized health, personalized therapy and personalized medicine. The conference started with a satellite meeting on genome-wide scan studies where the need for simplified models, the quality of the phenotypes and the input of epigenetics were dominant remarks. All of the omics approaches were then applied during the 3 days' sessions to multifactorial diseases (e.

Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases.

For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle.

Synthesis and biological evaluation of novel coumarin-based inhibitors of Cdc25 phosphatases.

The cell division cycle 25 (Cdc25) family of proteins are dual specificity phosphatases that activate cyclin-dependent kinase (CDK) complexes, which in turn regulate progression through the cell division cycle. Overexpression of Cdc25 proteins has been reported in a wide variety of cancers; their inhibition may thus represent a novel approach for the development of anticancer therapeutics. Herein we report new coumarin-based scaffolds endowed with a selective inhibition against Cdc25A and Cdc25C, being 6a and 6d the most efficient inhibitors and worthy of further investigation as anticancer agents.

eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development.

It is now widely recognized that translation factors are involved in cancer development and that components of the translation machinery that are deregulated in cancer cells may become targets for cancer therapy. The eukaryotic Release Factor 3 (eRF3) is a GTPase that associates with eRF1 in a complex that mediates translation termination. eRF3a/GSPT1 first exon contains a (GGC)n expansion coding for proteins with different N-terminal extremities.

Synthesis and antioxidant potential of novel synthetic benzophenone analogues.

Considering that oxidative stress is strongly implicated in the toxicity of chemotherapy, much effort is focused on the research of diverse antioxidants as protective agents. An efficient synthesis of three novel benzophenones containing 1,3-thiazol moiety (6a-c) is described. Their antioxidant power was evaluated in vitro and in three cell lines (the cancerous MCF7 and the non-cancerous hTERT-HME1 mammary cells, and the H9c2 cardiomyoblastic cells).

Apoptosis/necrosis switch in two different cancer cell lines: influence of benzoquinone- and hydrogen peroxide-induced oxidative stress intensity, and glutathione.

Depending on the strength of oxidative stress, cells exhibit proliferative, apoptotic or necrotic responses. We have investigated whether the severity of glutathione (GSH) depletion could determine the type of cell death using 1,4-benzoquinone (BQ) and H(2)O(2) in two different tumor cell lines (human mammary gland carcinoma MCF-7 and rat hepatoma H5-6). BQ-treated surviving cells showed an increase in GSH, but no detectable oxidized glutathione (GSSG) nor reactive oxygen species (ROS) augmentation.

Impact of chronic treatment with red wine polyphenols (RWP) on cerebral arterioles in the spontaneous hypertensive rat.

Several reports suggest that consumption of red wine is associated with a lower risk of stroke. We investigated the chronic effect of red wine polyphenols (RWP) on the functional and structural characteristics of cerebral arterioles in chronic hypertension, which is an important risk factor of stroke. Spontaneous hypertensive rats (SHR) were treated with RWP extract (100 mg/kg/day in drinking water) for 10 weeks.

Activity of novel Cdc25 inhibitors and preliminary evaluation of their potentiation of chemotherapeutic drugs in human breast cancer cells.

Dual-specific phosphatases Cdc25 play a critical role in the cell cycle regulation by activating kinases of Cdk/cyclin complexes. Three Cdc25 isoforms (A, B and C) have been identified in mammalians. Cdc25A and B display oncogenic properties and are over-expressed in different tumors.

Synthesis and protective effects of coumarin derivatives against oxidative stress induced by doxorubicin.

The use of doxorubicin (DOX) in the treatment of solid tumors is limited by cardiotoxicity essentially due to oxidative stress generation. The aim of this study was to identify coumarin derivatives displaying a protective antioxidant activity without affecting DOX antitumoral efficiency. A set of eighteen coumarinic derivatives was synthesized.

Interaction of the electrophilic ketoprofenyl-glucuronide and ketoprofenyl-coenzyme A conjugates with cytosolic glutathione S-transferases.

Carboxylic acid-containing drugs are metabolized mainly through the formation of glucuronide and coenzyme A esters. These conjugates have been suspected to be responsible for the toxicity of several nonsteroidal anti-inflammatory drugs because of the reactivity of the electrophilic ester bond. In the present study we investigated the reactivity of ketoprofenyl-acylglucuronide (KPF-OG) and ketoprofenyl-acyl-coenzyme A (KPF-SCoA) toward cytosolic rat liver glutathione S-transferases (GST).

Melatonin counteracts the loss of agonist-evoked contraction of aortic rings induced by incubation.

Incubation of aortic rings in a culture medium produces phenomena similar to those observed with aging, i.e. oxidative stress and inflammation leading to increased nitric oxide (NO)-mediated dilation and decreased arterial sensitivity to vasoconstrictor agents.