Targeting Intrinsic and Extrinsic Vulnerabilities for the Treatment of Multiple Myeloma

Multiple myeloma (MM) is a malignant plasma cell disorder, clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. Over the past decade, MM therapy is significantly improved by the introduction of novel therapeutics such as immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), monoclonal antibodies (daratumumab and elotuzumab), histone deacetylase (HDAC) inhibitors (Panobinostat). The clinical success of these agents has clearly identified vulnerabilities intrinsic to the MM cell- as well as targets that emanate from the tumor microenvironment. Despite these significant improvements, MM remains incurable due to the development of drug resistance. This perspective will discuss more recent strategies which take advantage of multiple targets within the proteome recycling pathway, chromatin remodeling, and disruption of nuclear export. In addition, we will review the development of strategies designed to block opportunistic survival signaling that occurs between the MM cell and the tumor microenvironment including strategies for inhibiting myeloma-induced immune suppression. It has become clear that MM tumors continue to evolve on therapy leading to drug resistance. It will be important to understand the mechanism and additional vulnerabilities that occur due to the development of clinical resistance

Copper complexes as chemical nucleases

Redox active mononuclear and binuclear copper(II) complexes have been prepared and structurally characterized. The complexes have planar N-donor heterocyclic bases like 1,10-phenanthroline (phen), dipyridoquinoxaline (dpq) and dipyridophenazine (dppz) ligands that are suitable for intercalation to B-DNA. Complexes studied for nuclease activity have the formulations [Cu(dpq)2(H2O)] (ClO4)2.H2O (1), [CuL(H2O)2(μ-ox)](ClO4)2 (L = bpy,2; phen,3; dpq,4; and dppz,5) and [Cu(L)(salgly)] (L = bpy,6; phen,7; dpq,8; and dppz,9), where salgly is a tridentate Schiff base obtained from the condensation of glycine and salicylaldehyde. The dpq complexes are efficient DNA binding and cleavage active species. The dppz complexes show good binding ability but poor nuclease activity. The cleavage activity of thebis-dpq complex is significantly higher than thebis-phen complex of copper(II). The nuclease activity is found to be dependent on the intercalating nature of the complex and on the redox potential of the copper(II)/copper(I) couple. The ancillary ligand plays a significant role in binding and cleavage activity

Antioxidant, analgesic and anti-inflammatory activities of Leucas cephalotes (Roxb.ex Roth) Spreng

The whole plant of the methanolic extract from Leucas cephalotes was screened for invitro antioxidant (using the DPPH method), invivo analgesic (using hot plate test in mice) and anti-inflammatory (using rat paw edema test) activities. The methanolic extract of Leucas cephalotes (MELC) scavenged the DPPH radicals in a dose-dependent manner. The IC50 value to scavenge DPPH radicals was found to be 421.3µg/ml. A significant (pO extrato metanólico total de Leucas cephalotes foi submetido à triagem para as atividades antioxidante in vitro (utilizando o método DPPH), analgésica (utilizando teste da placa quente, em camundongos) e antiinflamatória (utilizando teste de edema da pata de rato), nas doses de 200 e 400 mg/kg. O extrato metanólico de Leucas cephalotes (MELC) inativou radicais difenil picril hidrazila (DPPH) de forma dose-dependente. O IC50 para essa atividade foi de 421,3 µg/mL. Observou-se atividade analgésica significativa (

A-803467, A Tetrodotoxin-Resistant Sodium Channel Blocker, Modulates ABCG2-Mediated MDR In Vitro and In Vivo

ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant sodium channel blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of [3H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers

In vitro cytotoxicity of carbon nanoparticles against Hep G 32 cells

The aim of the present study was to evaluate the in vitro toxicity of two multi wall carbon nanotubes (MWCNT) on human hepatocytes (Hep G 32 cell lines). The toxic effects of carbon nanoparticles were analyzed after 48 h of incubation with Hep G 32 cells using MTT assay and also estimated the levels of LDH (that is leakage into the media). The results of the LDH estimation demonstrated that exposure of multi wall carbon nanotubes to hepatocytes (Hep G 32) for 48 h resulted in concentration-dependent increase in LDH leakage and exhibited a significant (p 50 or IC50 values (toxic concentration 50 i.e. concentration of particles inducing 50 %cell mortality) of two nanoparticles were found in the range of 36.99-37.15 μg/ml, which were less than that of quartz (known toxic agent, 39.85 μg/ml), indicating the toxic nature of carbon nanoparticlesColegio de Farmacéuticos de la Provincia de Buenos Aire

Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines

BCRP/ABCG2 emerged as an important multidrug resistance protein, because it confers resistance to several classes of cancer chemotherapeutic agents and to a number of novel molecularly-targeted therapeutics such as tyrosine kinase inhibitors. Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor used in the treatment of patients with advanced non small cell lung cancer (NSCLC) carrying activating EGFR mutations. Membrane transporters may affect the distribution and accumulation of gefitinib in tumour cells; in particular a reduced intracellular level of the drug may result from poor uptake, enhanced efflux or increased metabolism

Nutritional value, micronutrient and antioxidant capacity of some green leafy vegetables commonly used by southern coastal people of Bangladesh.

Southern coastal people of Bangladesh are highly vulnerable to food insecurity and malnutrition due to coastal flooding, deforestation and increased soil salinity. A number of green leafy vegetables are found in the southern coastal belt being traditionally eaten as daily basis by local people. But they are unaware of nutritional and medicinal use of these vegetables. To contribute to their wider utilization, five common vegetables namely Hibiscus sabdariffa, Trianthema portulacastrum, Diplazium esculentum, Heliotropium indicum L. and Hygrophila auriculata were selected for analysis of nutritional proximate, micronutrients and antioxidant potential. Nutritional properties were analyzed in terms of moisture, pH, protein, lipid, ash, fibre, minerals and carbohydrate. Total flavonoid, tannin and antioxidant capacity were evaluated using established protocols. The results demonstrated that collected plants are rich in carbohydrate, fibre, proteins, moisture and ash content but low in lipid content. The mineral elements were high with remarkable amount of Na (19.9-21.5 mg/gm), K (7.9-13.5 mg/gm) and P (1.0-1.8 mg/gm). All the samples were found to have considerable amount of flavonoid (90.6-144.5 mg QE/gm) and tannin content (26.8-57.2 mg GAE/gm). The IC50 value of DPPH and superoxide radical scavenging was the lowest for H. indicum (37.1 and 83.4 μg/ml, respectively) whereas T. portulacastrum possessed high reducing power (IC50 53.7 μg/ml). Among the five investigated species, T. portulacastrum and H. indicum were found to have good nutritional and antioxidant properties, thus can be promoted as a significant source of nutritional and antioxidant food supplements

Indoor MIMO Channels with Polarization Diversity: Measurements and Performance Analysis

This thesis deals with dual-polarized multiple input multiple output (MIMO) channels, an important issue for the practical deployment of multiple antenna systems. The MIMO architecture has the potential to dramatically improve the performance of wireless systems. Much of the focus of research has been on uni-polarized spatial MIMO configurations, the performance of which, is a strong function of the inter-element spacing. Thus the current trend of miniaturization, seems to be at odds with the implementation of spatial configurations in portable handheld devices. In this regard, dual-polarized antennas present an attractive alternative for realizing higher order MIMO architectures in compact devices. Unlike spatial channels, in the presence of polarization diversity, the subchannels of the MIMO channel matrix are not identically distributed. They differ in terms of average received power, envelope distributions, and correlation properties. In this thesis, we report on an indoor channel measurement campaign conducted at 2.4 GHz, to measure the copolarized and cross-polarized subchannels, under line-of-sight (LOS) and non-line-of-sight (NLOS) channel conditions. The measured data is then analyzed, to draw a fair comparison between spatial and dual-polarized MIMO systems, in terms of channel characteristics and achievable capacity. The main drawback of the MIMO architecture is that the gain in capacity comes at a cost of increased hardware complexity. Antenna selection is a technique using which we can alleviate this cost. We emphasize that this strategy is all the more relevant for compact devices, which are often constrained by complexity, power and cost. Using theoretical analysis and measurement results, this thesis investigates the performance of antenna selection in dual-polarized MIMO channels. Our results indicate that, antenna selection when combined with dual-polarized antennas, is an effective, low-complexity solution to the problem of realizing higher order MIMO architectures in compact devices.M.S.Committee Chair: Ingram Mary Ann; Committee Member: Durgin, Gregory David; Committee Member: Williams, Douglas