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Structural insight into DFMO resistant ornithine decarboxylase from Entamoeba histolytica: an inkling to adaptive evolution.

BACKGROUND: Polyamine biosynthetic pathway is a validated therapeutic target for large number of infectious diseases including cancer, giardiasis and African sleeping sickness, etc. α-Difluoromethylornithine (DFMO), a potent drug used for the treatment of African sleeping sickness is an irreversible inhibitor of ornithine decarboxylase (ODC), the first rate limiting enzyme of polyamine biosynthesis. The enzyme ODC of E. histolytica (EhODC) has been reported to exhibit resistance towards DFMO. METHODOLOGY/PRINCIPAL FINDING: The basis for insensitivity towards DFMO was investigated by structura

Polyamines inhibit the assembly of stress granules in normal intestinal epithelial cells regulating apoptosis.

Polyamines regulate multiple signaling pathways and are implicated in many aspects of cellular functions, but the exact molecular processes governed by polyamines remain largely unknown. In response to environmental stress, repression of translation is associated with the assembly of stress granules (SGs) that contain a fraction of arrested mRNAs and are thought to function as mRNA storage. Here we show that polyamines modulate the assembly of SGs in normal intestinal epithelial cells (IECs) and that induced SGs following polyamine depletion are implicated in the protection of IECs against apo

Methylglyoxal-bis(guanylhydrazone) (Methyl-GAG): current status and future prospects.

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs.

Endoplasmic Reticulum Stress is Involved in DFMO Attenuating Isoproterenol-Induced Cardiac Hypertrophy in Rats.

BACKGROUND/AIMS: Studies performed in experimental animals have shown that polyamines contribute to several physiological and pathological processes, including cardiac hypertrophy. This involves an increase in ornithine decarboxylase (ODC) activity and intracellular polyamines associated with regulation of gene expression. Difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, has attracted considerable interest for its antiproliferative role, which it exerts through inhibition of the polyamine pathway and cell turnover. Whether DFMO attenuates cardiac hypertrophy through endoplasmi

[Chemoprevention of colorectal cancer].

UNLABELLED: A NEW CONCEPT: Chemoprevention of cancer consists in the administration of chemical agents to prevent or inhibit carcinogenesis. This strategy can be applied at any stage of carcinogenesis. ASSESSMENT: The development of such agents relies on classical bases: phases I, II and III. The approach consists in assessing the effect of the substance tested in patients with history of resected adenomas of the colon and at high risk of relapse and/or family risk of colon cancer. THE PRINCIPLE AGENTS UNDER ASSESSMENT: Are aspirin, type 2 cyclo-oxygenase inhibitors, calcium, folic acid, cer

Development of difluoromethylornithine (DFMO) as a chemoprevention agent.

D,L-alpha-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It was hoped that this enzyme-activated, irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis, would be effective as a chemotherapy for hyperproliferative diseases, including cancer and/or infectious processes. DFMO was generally found to exert cytostatic effects on mammalian cells and tissues, and its effectiveness as a therapeutic agent has been modest. DFMO was also found to cause treatment-limiting (but reversible) ototoxicity at high doses. This side effect, along with its min

Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care?

Despite significant progress in cancer prevention, screening, and treatment, the still limited number of therapeutic options is an obstacle towards increasing the cancer cure rate. In recent years, many efforts were put forth to develop therapeutics that selectively target different components of the oncogenic Wnt/β-catenin signaling pathway. These include small molecule inhibitors, antibodies, and more recently, gene-based approaches. Although some of them showed promising outcomes in clinical trials, the Wnt/β-catenin pathway is still not targeted in routine clinical practice for cancer mana

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… However, in a phase III clinical study in patients with Familial Adenomatous Polyposis (FAP) ( NCT01483144 ), the eflornithine-sulindac combination did not significantly reduce disease progression rate compared with eflornithine alone [ 156 ]. … In addition, the DVL inhibitor sulindac prevents malignant transformation in patients with FAP when combined with eflornithine [ 156 ]. Some Wnt/β-catenin inhibitors also showed promising anticancer activity when used as monotherapy in specific contexts. …

Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy.

Our previous study has demonstrated that dietary arginine supplementation during early pregnancy enhanced embryo implantation in rats. However, the mechanism was not clear. The objective of this study was to determine the mechanism that arginine enhanced embryo implantation during early pregnancy. Rats were fed the basal diets supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) once pregnancy. On d4 of pregnancy, rats were given intrauterine injection of L-NG-nitro arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), α-difluoromethylorni

Beyond tamoxifen new endpoints for breast cancer chemoprevention, new drugs for breast cancer prevention.

Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled

Alpha-difluoromethylornithine induction of apoptosis: a mechanism which reverses pre-established cell proliferation and cancer initiation in esophageal carcinogenesis in zinc-deficient rats.

Alpha-difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis. Previous work showed simultaneous administration of DFMO and a zinc-deficient (ZD) diet to weanling rats from the beginning inhibited the onset of zinc-deficiency-induced esophageal cell proliferation by activating apoptosis and reduced the incidence of N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer. Because esophageal cancer initiation by NMBA is very rapid in ZD rats, this study determined whether DFMO is effective in preventing esophageal carcin

Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism.

Type 2 cytokines regulate fibrotic liver pathology in mice infected with Schistosoma mansoni. Switching the immune response to a type 1-dominant reaction has proven highly effective at reducing the pathologic response. Activation of NOS-2 is critical, because type 1-deviated/NO synthase 2 (NOS-2)-deficient mice completely fail to control their response. Here, we demonstrate the differential regulation of NOS-2 and arginase type 1 (Arg-1) by type 1/type 2 cytokines in vivo and for the first time show a critical role for arginase in the pathogenesis of schistosomiasis. Using cytokine-deficient m

Keyword Index for Volume 108

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… docosahexaenoic acid 486 Down syndrome 2334 doxifluridine 1245 DPYS 2505 drug resistance 1810 ductal intraepithelial neoplasia 1593 dying 1942 E2F1 1470 E3 ligases 2495 E7 450 early deaths 681 early diagnosis 2045 early stage 1348 EBP1 557 E-cadherin 402 eEF1A2 2304 effect size 1790 eflornithine …

Targeted therapies in pediatric oncology: A start.

The treatment of cancers was revolutionized by the use of combination "conventional" chemotherapy, first in children, during the 20th century. That foundation of therapy, while having achieved significant advances in survival, has reached its limits. Innovations in targeted therapies are now building upon that foundation to further improve outcomes in pediatric oncology. These targeted agents are designed to narrowly utilize specific biologic processes for greater efficacy and optimally fewer generalized toxicities. I will provide an overview of the current spectrum of targeted therapies avail

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… Inhibition of these pathways seemed to potentiate the effects of the retinoids, and vice versa. 398 , 399 , 400 , 401 , 402 Difluoromethylornithine (DFMO), also known as eflornithine, is an inhibitor of ODC used against the parasites that cause trypanosomiasis. 403 Researchers showed it was efficacious … , relapsed from, or contraindicated to anthracycline chemotherapy Bapna et al. 382 ; Tallman et al. 383 ; Zheng et al. 384 ; Kutny et al. 385 ; Kutny et al. 386 ; Zhang et al. 387 ; Kutny et al. 388 Isotretinoin differentiation agent RARA high-risk neuroblastoma, with dinutuximab Matthay et al. 392 Eflornithine …

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021.

The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition ("first-in-indication"), (2) first drug using a novel molecular mechanism ("first-in-class"), and (3) "next-in-class", i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indicati

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… Besides the advantage of oral application route, fexinidazole obviates the need for hospital treatment and is much less toxic compared to the earlier standard therapy with eflornithine and nifurtimox (Hidalgo et al. 2021 ). … Efficacy and toxicity of fexinidazole and nifurtimox plus eflornithine in the treatment of African trypanosomiasis: a systematic review. Cureus. 2021;13:e16881–e16881. doi: 10.7759/cureus.16881. …

Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein-Drug and Protein-Protein Structures: An Analysis of Kinetically Active Residues.

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic s

Drug reprofiling history and potential therapies against Parkinson's disease.

Given the high whittling down rates, high costs, and moderate pace of new medication, revelation, and improvement, repurposing "old" drugs to treat typical and uncommon illnesses is progressively becoming an appealing proposition. Drug repurposing is the way toward utilizing existing medications in treating diseases other than the purposes they were initially designed for. Faced with scientific and economic challenges, the prospect of discovering new medication indications is enticing to the pharmaceutical sector. Medication repurposing can be used at various stages of drug development, althou

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… | 2004 14 | Duloxetine | Antidepressant/GAD | Eli Lilly | Stress urinary incontinence | Eli Lilly | 2004 ------------ | --------- | | Fibromyalgia | Eli Lilly | 2008 | | | Musculoskeletal pain | Eli Lilly | 2010 15 | Donepezil | Alzheimer’s disease | Eisai | Dementia | Eisai/Pfizer | 2006 16 | Eflornithine …

Drugs and Epigenetic Molecular Functions. A Pharmacological Data Scientometric Analysis.

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in c

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… Inflammation, pain | [ 21 ] Cocaine | Voltage-gated sodium channel | Decreased expression of histone methyltransferase G9a and subsequent lower methylation levels at H3K9 | Local anesthetic | [ 63 ] Disulfiram | Aldehyde dehydrogenase | DNA methyltransferase (DNMT) inhibitor | Prostate cancer | [ 64 ] Eflornithine …

Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer.

The strategy of using existing drugs originally developed for one disease to treat other indications has found success across medical fields. Such drug repurposing promises faster access of drugs to patients while reducing costs in the long and difficult process of drug development. However, the number of existing drugs and diseases, together with the heterogeneity of patients and diseases, notably including cancers, can make repurposing time consuming and inefficient. The key question we address is how to efficiently repurpose an existing drug to treat a given indication. As drug efficacy rem

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… In 2013 a phase III double blind placebo-controlled trial of Sulindac and Eflornithine to prevent recurrence of high-risk adenomas and second primary stage 0 to III of CRC patients was initiated ( NCT01349881 ). … Enrolled patients underwent curative surgery and were treated with Sulindac or Eflornithine for 36 months with a subsequent 5-year follow up period. The results are pending. …

Dermatologic conditions in women receiving systemic cancer therapy.

As advances in cancer therapies have improved cancer-related survival, novel therapeutics have also introduced a variety of dermatologic toxicities, and an increased number of patients are living with these sequalae. Women with cancer in particular experience a spectrum of dermatologic conditions that affect their skin, hair, nail, and mucosal surfaces. Studies have shown that these toxic effects can significantly affect quality of life and alter a woman's self-image, cultural identity, femininity, sexuality, and mental health. In severe instances, dermatologic toxicities may even disrupt canc

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… For hirsutism, women may opt to shave or pluck their upper lip hairs, but in severe cases, topical eflornithine or laser hair removal can be trialed to slow the growth of terminal hairs or ( Macdonald et al., 2015 ). …