The Role of β-Elimination for the Clinical Activity of Hypomethylating Agents and Cyclophosphamide Analogues

A beta-elimination reaction generally involves the cleavage of a sigma (σ) bond at the position beta (β) to a pair of electrons that departs a molecule via a nucleophilic leaving group, subsequently leading to the formation of a new pi (π) bond. We describe the importance of β-elimination reactions in the mechanisms of action of two classes of chemotherapeutic agents. First, we evaluate the chemical steps resulting in formation of 5-methyl-cytosine and its disassociation from DNA methytransferase (DNMT) by b­-elimination reaction. When carbon 5 (C5) of cytosine is substituted with a nitrogen atom (N) in 5-aza-cytosine analogues, the critical β-elimination reaction cannot proceed, which results in the permanent attachment of 5-aza-cytosine to DNMT. The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of β-elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing β-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical β-elimination reaction. This ultimately culminates in a selective cytotoxic effect of these agents against lymphocytes, but not against hematopoietic and other stem cells with high aldehyde dehydrogenase content

Dual targeting of glutamine and serine metabolism in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia-derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR-Cas9-mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC50) for Rylaze, indicating heightened sensitivity to crisantaspase therapy. Treatment of AML cells with a combination of Rylaze and a small molecule inhibitor of PHGDH (BI4916) revealed synergistic anti-proliferative effects in both cell lines and primary AML patient samples. Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML

Controlled Drug Delivery Systems by functionalized silica-based nanoparticles.

Abstract Introduction: : Mesoporous silica are solid materials that show the potential for a variety of controlled drug delivery applications because of some unique properties including porous, high surface area(900M2/g), pore volumes(0.9CM3/g), regular pore size with uniform distribution (2-10nm), chemical and thermal stability and biocompatibility and biodegradation. In this case, MCM-41 has the ability of loading more drug because pf larger pores. This amount of drug has increased by functionalizing the surface despite of decreasing the surface area. Methods and Results: The Methods section should provide enough information to in this study after providing MCM-41 and functionalizing it with amino propyl,the procedure of soaking and eliminating (evaporating) the solvent were used for loading drug. For insuring of the loading drug and determination of loading ratio we used infrared spectroscopy (indirect) and x-ray diffraction (XRD) and BET way.Finally, the studies about drug release from system have been done in an environment simulated gastric and intestine fluid PH. In this article, Diclofenac sodium and Piroxicam as the sample and MCM-41 and functionalized MCM-41 as the carrier were used. Conclusions: the drugs were released faster than the formulation that were produced from the eliminating procedure because drugs were more on surface. In this study, the effect of functionalizing the surface on drug release was not significant

A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

BACKGROUND: Dimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhanced or suppressed growth in the presence of binaphthoquinones. METHODOLOGY/PRINCIPAL FINDINGS: Exposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growth with IC(50)s in the microM range. Drug sensitivity and resistance screens were performed by exposing arrays of a haploid yeast deletion mutant library to BiQs at concentrations near their IC(50). Sensitivity screens identified yeast with deletions affecting mitochondrial function and cellular respiration as having increased sensitivity to BiQs. Corresponding to this, wild type yeast grown in the absence of a fermentable carbon source were particularly sensitive to BiQs, and treatment with BiQs was shown to disrupt the mitochondrial membrane potential and lead to the generation of reactive oxygen species (ROS). Furthermore, baseline ROS production in BiQ sensitive mutant strains was increased compared to wild type and could be further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydrogenase, NDE1, as critical to BiQ toxicity and over-expression of this gene resulted in increased ROS production and increased sensitivity of wild type yeast to BiQ. CONCLUSIONS/SIGNIFICANCE: In yeast, binaphthoquinone cytotoxicity is likely mediated through NAD(P)H:quonine oxidoreductases leading to ROS production and dysfunctional mitochondria. Further studies are required to validate this mechanism in mammalian cells

A U-shaped relationship between haematocrit and mortality in a large prospective cohort study

Background: Only a limited number of studies have investigated the correlation between haematocrit (HCT) and mortality in the general population, and few of those studies have had data on a wide range of low and high levels of HCT. We investigated the association between baseline HCT and mortality in a prospective cohort study of 49 983 adult subjects in Iran with a broad spectrum of HCT values. Methods: Data on socio-demographic and life-style factors, past medical history, and levels of HCT were collected at enrollment. During a mean follow-up of 5 years (follow-up success rate ±99%), 2262 deaths were reported. Cox proportional hazards regression models were used to estimate hazard ratios and corresponding 95% confidence intervals. Results: There was a U-shaped relationship between categories of HCT and mortality in both sexes: both low and high levels of HCT were associated with increased overall mortality and mortality from cardiovascular disease. The U-shaped relationship persisted after several sensitivity analyses were done, including analyses restricted to non-smokers and non-users of opium; analyses excluding deaths from accidents and other external causes as well as deaths of persons with self-reported ischemic heart disease at the baseline interview for the study; and analyses excluding the first 2 years of follow-up. Self-reported past medical history and lack of data about lipids and other cellular blood components were the major limitations of the study. Conclusions: Low and high levels of HCT are associated with increased mortality in the general population. The findings in the present study can be of particular importance for low- and middle-income countries in which a substantial proportion of the population lives with suboptimal levels of HCT. © Published by Oxford University Press on behalf of the International Epidemiological Association 2013

Vitamin and Mineral Supplements: Do We Really Need Them?

In the United States, 40 – 50% of the men and women 50 years of age or older regularly use multivitamin/mineral (MVM) supplements, making the annual sales of these supplements over $11 billion. However, the question remains whether using MVM supplements is beneficial to health. This article reviews the results of randomized studies of MVM supplements and individual vitamins/mineral supplements in relation to overall mortality and incidence of chronic diseases, particularly cancer and ischemic heart disease. The results of large-scale randomized trials show that, for the majority of the population, there is no overall benefit from taking MVM supplements. Indeed, some studies have shown increased risk of cancers in relation to using certain vitamins

1-C Metabolism—Serine, Glycine, Folates—In Acute Myeloid Leukemia

Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. Glutamine depletion has also emerged as a therapeutic approach for cancers that have demonstrated dependence on glutamine for survival. Recent studies have shown that in response to glutamine deprivation leukemia cells upregulate key enzymes in the serine biosynthesis pathway, suggesting that serine upregulation may be a targetable compensatory mechanism. These new findings may provide opportunities for novel cancer treatments

Anti-Viral Multi-Quinone Compounds and Regiospecific Synthesis Thereof

This invention provides various biquinone and trimeric quinone derivatives. The invention also provides a method for synthesis of a multi-quinone compound including reacting a hydroxyquinone anion with a first quinone possessing a first directing group at a C-2 of the first quinone and a second directing group at a C-3 of the first quinone and obtaining a biquinone having one of the first and second directing groups at a C-3 of a first quinone monomer and a hydroxyl group at a C-3' of a second quinone monomer. The biquinone can be further reacted to obtain various biquinone derivatives or with a second hydroxyquinone anion to obtain trimeric quinone derivatives, including trimeric naphthoquinone derivatives. The biquinones and trimeric quinones of this invention demonstrate antiviral activity and can be used to treat viral infections, particularly HIV infections.Sponsorship: Illinois Institute of TechnologyUnited States Paten

Case Report Reverse Pseudohyperkalemia: An Important Clinical Entity in Chronic Lymphocytic Leukemia

Hyperkalemia is a potentially lethal electrolyte derangement commonly seen in patients with hematologic neoplasms with or without renal failure. Pseudohyperkalemia and reverse pseudohyperkalemia also can be seen in this patient population and early recognition and diagnosis of these conditions are vital. Here, we report a case of reverse pseudohyperkalemia in a patient with chronic lymphocytic leukemia (CLL) and provide recommendations regarding diagnostic and therapeutic strategies for management of such patients. Further, we discuss the pathogenesis of this condition and its potential role as a surrogate of favorable prognostic features in patients with CLL