Enhancing anti-inflammatory effect of brucine nanohydrogel using rosemary oil: a promising strategy for dermal delivery in arthritic inflammation.

Brucine (BRU), an active constituent of Strychnos nux-vomica L., is one of the potential agents to control subside swelling in arthritis. However, its hydrophobic nature, poor permeation, shorter half-life, narrow therapeutic window, and higher toxicity impede its clinical applications. Hence, this investigation was aimed to develop and evaluate novel BRU loaded ß-cyclodextrin (ß-CD) nanosponges (BRUNs) hydrogel consisting rosemary essential oil (RO), which have been tailored for delayed release, enhanced skin permeation, and reduced irritation, while retaining anti-oxidant and anti-inflammatory activities of this bioactive. Firstly, BRUNs were fabricated by melt technique and characterized appropriately. BRUNs6 demonstrated two fold enhancement in BRU solubility (441.692 ± 38.674) with minimum particle size (322.966 ± 54.456) having good PDI (0.571 ± 0.091) and zeta potential (-14.633 ± 6.357). In vitro release results demonstrated delayed release of BRU from BRUNs6 (67 ± 4.25%) over 24 h through molecular diffusion mechanism. Further, preserved anti-inflammatory (53.343 ± 0.191%) and antioxidant potential (60.269 ± 0.073%) of bioactive was observed in BRUNs6. Hence, this Ns batch was engrossed with Carbopol®934 hydrogel with RO and characterized. In vitro (release and anti-inflammatory activity), ex-vivo (skin permeability) and in vivo (carrageenan-induced inflammation) assays along with irritation study were conducted for fabricated hydrogels. Results revealed that in vitro release of BRU was further delayed from Ns hydrogel with RO (56.45 ± 3.01%) following Fickian mechanism. Considerable enhancement in skin permeability (60.221 ± 0.322 µg/cm2/h) and preservation of anti-inflammatory activity (94.736 ± 2.002%) was also observed in BRUNs6 hydrogel containing RO. The irritation of BRU was found reduced (half) after its entrapped in Ns. Further, as a proof of concept, BRUNs6 hydrogel with RO effectively reduced (75.757 ± 0.944%) carrageenan-induced inflammation in rat model in comparison to pure BRU (54.914 ± 1.081%). Hence, BRUNs hydrogel with RO can be considered as a promising alternative for dermal delivery of BRU in arthritis.

Solid Lipid Nanoparticles Embedded Hydrogels as a Promising Carrier for Retarding Irritation of Leflunomide.

Leflunomide (LEF), a disease-modifying anti-rheumatic drug, has been widely explored for its anti-inflammatory potential in skin disorders such as psoriasis and melanoma. However, its poor stability and skin irritation pose challenges for topical delivery. To surmount these issues, LEF-loaded solid lipid nanoparticles (SLNs) integrated with hydrogels have been developed in the present investigation. SLNs developed by microemulsion techniques were found ellipsoidal with 273.1 nm particle size and -0.15 mV zeta potential. Entrapment and total drug content of LEF-SLNs were obtained as 65.25 ± 0.95% and 93.12 ± 1.72%, respectively. FTIR and XRD validated the successful fabrication of LEF-SLNs. The higher stability of LEF-SLNs (p < 0.001) compared to pure drug solution was observed in photostability studies. Additionally, in vitro anti-inflammatory activity of LEF-SLNs showed good potential in comparison to pure drugs. Further, prepared LEF-SLNs loaded hydrogel showed ideal rheology, texture, occlusion, and spreadability for topical drug delivery. In vitro release from LEF-SLN hydrogel was found to follow the Korsmeyer-Peppas model. To assess the skin safety of fabricated lipidic formulation, irritation potential was performed employing the HET-CAM technique. In conclusion, the findings of this investigation demonstrated that LEF-SLN hydrogel is capable of enhancing the photostability of the entrapped drug while reducing its skin irritation with improved topical delivery characteristics.

Formulation Strategies for Enhancing Pharmaceutical and Nutraceutical Potential of Sesamol: A Natural Phenolic Bioactive.

Natural plants and their products continue to be the major source of phytoconstituents in food and therapeutics. Scientific studies have evidenced the benefits of sesame oil and its bioactives in various health conditions. Various bioactives present in it include sesamin, sasamolin, sesaminol, and sesamol; among these, sesamol represents a major constituent. This bioactive is responsible for preventing various diseases including cancer, hepatic disorders, cardiac ailments, and neurological diseases. In the last decade, the application of sesamol in the management of various disorders has attracted the increasing interest of the research community. Owing to its prominent pharmacological activities, such as antioxidant, antiinflammatory, antineoplastic, and antimicrobial, sesamol has been explored for the above-mentioned disorders. However, despite the above-mentioned therapeutic potential, its clinical utility is mainly hindered owing to low solubility, stability, bioavailability, and rapid clearance issues. In this regard, numerous strategies have been explored to surpass these restrictions with the formulation of novel carrier platforms. This review aims to describe the various reports and summarize the different pharmacological activities of sesamol. Furthermore, one part of this review is devoted to formulating strategies to improve sesamol's challenges. To resolve the issues such as the stability, low bioavailability, and high systemic clearance of sesamol, novel carrier systems have been developed to open a new avenue to utilize this bioactive as an efficient first-line treatment for various diseases.

Formulation, Characterization, Anti-Inflammatory and Cytotoxicity Study of Sesamol-Laden Nanosponges.

Sesamol (SES) possesses remarkable chemotherapeutic activity, owing to its anti-inflammatory and antioxidant potential. However, the activity of SES is mainly hampered by its poor physicochemical properties and stability issues. Hence, to improve the efficacy of this natural anti-inflammatory and cytotoxic agent, it was loaded into ß-cyclodextrin nanosponges (NS) prepared using different molar ratios of polymer and crosslinker (diphenyl carbonate). The particle size of SES-laden NS (SES-NS) was shown to be in the nano range (200 to 500 nm), with a low polydispersity index, an adequate charge (-17 to -26 mV), and a high payload. Field emission scanning electron microscopy, thermogravimetric analysis, and Fourier transform infrared spectroscopy were used to characterize the bioactive-loaded selected batch (SES-NS6). This batch of nanoformulations showed improved solubilization efficacy (701.88 µg/mL) in comparison to bare SES (244.36 µg/mL), polymer (ß-CD) (261.43 µg/mL), and other fabricated batches. The drug release data displayed the controlled release behavior of SES from NS. The findings of the egg albumin denaturation assay revealed the enhanced anti-inflammatory potential of SES-NS as compared to bare SES. Further, the cytotoxicity assay showed that SES-NS was more effective against B16F12 melanoma cell lines than the bioactive alone. The findings of this assay demonstrated a reduction in the IC50 values of SES-NS (67.38 µg/mL) in comparison to SES (106 µg/mL). The present investigation demonstrated the in vitro controlled release pattern and the enhanced anti-inflammatory and cytotoxic activity of SES-NS, suggesting its potential as a promising drug delivery carrier for topical delivery.

Evaluation of solubility, photostability and antioxidant activity of ellagic acid cyclodextrin nanosponges fabricated by melt method and microwave-assisted synthesis.

Ellagic acid (EA) is a polyphenolic bioactive with a wide range of pharmacological activities. Regrettably, it possesses poor solubility, stability and permeability (in the gastrointestinal tract); and first-pass metabolism. Therefore, to address these challenges, the present research was aimed to encapsulate EA in cyclodextrin nanosponges (CDNS). Herein, the melt method and microwave-assisted technique have been employed for crafting CDNS. EA was loaded in CDNS via freeze-drying, followed by appropriate characterization. EA-CDNS were also assessed for encapsulation, particle size, zeta potential, and polydispersity index, which presented satisfactory results. In vitro, antioxidant activity was conducted using the DPPH (2, 2-diphenyl-1-picrylhydrazyl) assay. The solubilization efficacy of EA was analyzed in distilled water and compared with CDNS, which demonstrated ten folds augmentation for the selected batch. A remarkable improvement in the photostability of EA was also observed after its inclusion. In nutshell, the results demonstrated the superiority of the melt method in terms of solubility, entrapment, photostability, and antioxidant potential.

Ecofriendly Ethyl Cellulose Microsponges of Citronella Oil: Preparation, Characterization and Evaluation of Cytotoxicity and Larvicidal assay.

BACKGROUND: Citronella Oil (CO) was used by the Indian army as mosquito repellant to repel mosquitoes at the beginning of the 20th century and later in 1948, it was registered in the USA for commercial purposes. Due to its ecofriendly nature, CO possesses immense potential as a mosquito repellent. METHODS: Citronella oil is a valuable alternative to synthetic mosquito repellents commonly used nowadays. However, its volatile nature, poor stability in air and high temperature restrict its application. Its direct application on skin may lead to skin irritation. To surmount the above-mentioned issues, the present research aims to develop Microsponge (MS), a novel dosage form for enhancing the utility and safety of CO. Quasi emulsion solvent diffusion method was chosen for crafting MS using ethyl cellulose with various drug-polymer ratios and characterized. In vitro cytotoxicity evaluation was also carried out to check the dermal safety of COMS. RESULTS: The present results revealed that the size of all prepared formulation lies in the micro range (20 ± 3 to 41 ± 4 µm), with good payload (42.09± 3.24 to 67.08± 6.43%). The results of FE-SEM depicted that MS were spherical in shape with porous nature. Cytotoxicity results indicated that COMS were safe on skin cells, when compared to pure CO. The optimized MS were also assessed for larvicidal assay against larvae of Anopheles culicifacies. CONCLUSION: The CO micro-formulations were found to possess enhanced stability of this oil. Entrapment of CO in MS resulted in a better vehicle system in terms of safety, stability and handling benefits of this oil.

Enhanced anti-psoriatic efficacy and regulation of oxidative stress of a novel topical babchi oil (Psoralea corylifolia) cyclodextrin-based nanogel in a mouse tail model.

Psoriasis is a proliferative inflammatory skin disorder with relapsing episodes. Herein, the efficacy of babchi oil (BO) loaded nanostructure gel was evaluated for antipsoriatic activity and oxidative stress biomarkers assessment using mouse tail model. BO was entrapped into cyclodextrin-based nanocarriers (360.9 ± 19.55 nm), followed by incorporation into Carbopol gel and characterised for viscosity, spreadability, and texture analysis. The gels were topically applied on mouse-tails once daily for fourteen days. Evaluation of antipsoriatic activity as determined by histopathological observations of orthokeratotic epidermis revealed two times higher efficacy of BO nanogel in comparison to the native BO gel. Further, significantly enhanced superoxide dismutase (SOD) and reduced glutathione (GSH) levels, and diminished malondialdehyde (MDA) and nitrite (NO) levels revealed that prepared nanogels played a major role in the management of reactive oxygen species (ROS) associated in psoriasis pathogenesis. Hence, this study provides strong evidence for use of cyclodextrin-based nanogels as a safe and better delivery carrier of BO for management of psoriasis.

Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells.

p97 is an ATPase that works in concert with histone deacetylase 6 (HDAC6), to facilitate the degradation of misfolded proteins by autophagosomes. p97 has also been implicated in DNA repair and maintaining genomic stability. In this study, we determined the effect of combined inhibition of p97 and HDAC6 activities in mantle cell lymphoma (MCL) cells. We report that treatment with p97 inhibitors induces dose-dependent apoptosis in MCL cells. The p97 inhibitor CB-5083 induces ER stress markers GRP78 and CHOP and results in the accumulation of polyubiquitylated proteins. Co-treatment with CB-5083 and the HDAC6 inhibitor ACY-1215 result in marked downregulation of CDK4, Cyclin D1, and BRCA1 levels without inhibiting autophagic flux. Consequently, treatment with CB-5083 accentuates DNA damage in response to treatment with ACY-1215 resulting in enhanced accumulation of H2AX-γ and synergistic apoptosis. Furthermore, ATM loss severely impairs phosphorylation of 53BP1 following co-treatment with CB-5083 and ACY-1215 in response to gamma irradiation. Finally, co-treatment CB-5083 and ACY-1215 results in reduced tumor volumes and improves survival in Z138C and Jeko-1 xenografts in NSG mice. These observations suggest that combined inhibition of p97 and HDAC6 abrogates resolution of proteotoxic stress and impairs DNA repair mechanisms in MCL cells.

Encapsulation of babchi essential oil into microsponges: Physicochemical properties, cytotoxic evaluation and anti-microbial activity.

Babchi essential oil (BEO) is a valuable essential oil reported to possess a variety of biological activities such as antitumor, anti inflammatory, immunomodulatory, antioxidant, antifungal and antibacterial properties. Due to its anti-microbial properties, this oil possesses an immense potential for the treatment of dermatological disorders. Further, it has minimal tendency to develop resistance, a common issue with most of the antibiotics. However, its highly viscous nature and poor stability in the presence of light, air and high temperature, limits its practical applications. To surmount these issues, this research aims to encapsulate BEO in ethyl cellulose (EC) microsponges for enhanced stability, antibacterial effect and decreased dermal toxicity. The quasi emulsion solvent evaporation technique was used for fabrication of the BEO microsponges employing EC as polymer, polyvinyl alcohol (PVA) as stabilizer and dichloro methane (DCM) as solvent. The effect of formulation variables such as the amount of EC and PVA were also investigated. The prepared microformulations were evaluated for production yield, encapsulation efficiency, particle size and in vitro release. In vitro cytotoxicity was also checked to assess dermal safety of BEO microsponges. Results revealed that all the dispersions were in micro size range (20.44 ± 3.13 µm to 41.75 ± 3.65 µm), with good encapsulation efficiency (87.70 ± 1.20% of F2) and controlled release profile (cumulative drug release 73.34 ± 1.76%). Field emission scanning electron microscopy results showed that the microsponges possessed a spherical uniform shape with a spongy structure. Results of cytotoxicity study indicated that the prepared microsponges were safer on dermal cells in comparison to pure BEO. The optimized formulation was also evaluated for in vitro antimicrobial assay against dermal bacteria like Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, which confirmed their enhanced antibacterial activity. Furthermore, the results of photostability and stability analysis indicated improved stability of BEO loaded microsponges. Hence, encapsulation of BEO in microsponges resulted in efficacious carrier system in terms of stability as well as safety of this essential oil alongwith handling benefits.

Therapeutic Potential of Citronella Essential Oil: A Review.

Mosquito-borne diseases such as malaria, filariasis, chikunguniya, yellow fever, dengue and Japanese encephalitis are the major cause of remarkable morbidity and mortality in livestock and humans worldwide. Since ancient times, aromatic plants are used for their medicinal value. Essential oils derived from these plants may be used as effective alternatives/adjuvants in pharmaceuticals, biomedical, cosmetic, food, veterinary and agriculture applications. These oils have also gained popularity and interest for prevention and treatment of various disorders. However, several reports on adverse effects including skin eruption, contact artricaria or toxic encephalopathy in children are available for synthetic repellent in the literature. Thus, natural insect repellents like essential oils have been explored recently as an alternative. One such essential oil studied widely, is citronella oil, extracted mainly from Cymbopogon nardus. This essential oil has exhibited good efficacy against mosquitoes. It is a mixture of components including citronellal, citronellol, geraniol as major constituents contributing to various activities (antimicrobial, anthelmintic, antioxidant, anticonvulsant antitrypanosomal and wound healing), besides mosquito repellent action. Citronella essential oil is registered in US EPA (Environmental protection agency) as insect repellent due to its high efficacy, low toxicity and customer satisfaction. However, poor stability in the presence of air and high temperature limits its practical applications. Since specific knowledge on properties and chemical composition of oil is fundamental for its effective application, the present review compiles and discusses biological properties of citronella oil. It also sheds light on various formulations and applications of this essential oil.

Encapsulation of Babchi Oil in Cyclodextrin-Based Nanosponges: Physicochemical Characterization, Photodegradation, and In Vitro Cytotoxicity Studies.

Babchi (Psoralea corylifolia) oil is an important essential oil used in several traditional medicines to cure various disorders. This phytotherapeutic agent possesses a number of pharmacological activities including antibacterial, antifungal, antioxidant, anti-inflammatory, immunomodulatory, and antitumor factors. However, volatile nature, poor stability, and solubility of babchi oil (BO) restrict its pharmaceutical applications. Therefore, the aim of the present work was to encapsulate this oil in ß-cyclodextrin nanosponges (NS) in order to overcome the above limitations. To fabricate nanosponges, ß-cyclodextrin was cross-linked with diphenyl carbonate in different molar ratios viz. 1:2, 1:4, 1:6, 1:8, and 1:10. The blank nanosponges were loaded with BO using the freeze-drying method. The particle size of the BO loaded nanosponges was found to lie between 200 and 500 nm with low polydispersity index. Furthermore, the zeta potential, the Fourier transform infrared spectroscopy, X-ray diffraction, thermal analysis, and electron microscopy were carried out for characterization of BO nanosponges. Results obtained from spectral analysis ascertained the formation of inclusion complexes. Additionally, solubilisation efficiency of BO was checked in distilled water and found enhanced by 4.95 times with optimized ß-cyclodextrin nanosponges. The cytotoxicity study was carried out by the MTT assay using HaCaT cell lines. A significant improvement in photo-stability of essential oil was also observed by inclusion innanosponges. Lastly, the optimized formulation was tested for antibacterial activity using Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Therefore, encapsulation of BO in nanosponges resulted in efficacious carrier system in terms of solubility, photo-stability, and safety of this oil along with handling benefits.

Nanotherapeutics: An insight into healthcare and multi-dimensional applications in medical sector of the modern world.

In recent years nanotechnology has revolutionized the healthcare strategies and envisioned to have a tremendous impact to offer better health facilities. In this context, medical nanotechnology involves design, fabrication, regulation, and application of therapeutic drugs and devices having a size in nano-range (1-100 nm). Owing to the revolutionary implications in drug delivery and gene therapy, nanotherapeutics has gained increasing research interest in the current medical sector of the modern world. The areas which anticipate benefits from nano-based drug delivery systems are cancer, diabetes, infectious diseases, neurodegenerative diseases, blood disorders and orthopedic problems. The development of nanotherapeutics with multi-functionalities has considerable potential to fill the lacunae existing in the present therapeutic domain. Nanomedicines in the field of cancer management have enhanced permeability and retention of drugs thereby effectively targeting the affected tissues. Polymeric conjugates of asparaginase, polymeric micelles of paclitaxel have been recmended for various types of cancer treatment .The advancement of nano therapeutics and diagnostics can provide the improved effectiveness of the drug with less or no toxicity concerns. Similarly, diagnostic imaging is having potential future applications with newer imaging elements at nano level. The newly emerging field of nanorobotics can provide new directions in the field of healthcare. In this article, an attempt has been made to highlight the novel nanotherapeutic potentialities of polymeric nanoparticles, nanoemulsion, solid lipid nanoparticle, nanostructured lipid carriers, dendrimers, nanocapsules and nanosponges based approaches. The useful applications of these nano-medicines in the field of cancer, nutrition, and health have been discussed in details. Regulatory and safety concerns along with the commercial status of nanosystems have also been presented. In summary, a successful translation of emerging nanotherapeutics into commercial products may lead to an expansion of biomedical science. Towards the end of the review, future perspectives of this important field have been introduced briefly.

Targeting p97 to Disrupt Protein Homeostasis in Cancer.

Cancer cells are addicted to numerous non-oncogenic traits that enable them to thrive. Proteotoxic stress is one such non-oncogenic trait that is experienced by all tumor cells owing to increased genomic abnormalities and the resulting synthesis and accumulation of non-stoichiometric amounts of cellular proteins. This imbalance in the amounts of proteins ultimately culminates in proteotoxic stress. p97, or valosin-containing protein (VCP), is an ATPase whose function is essential to restore protein homeostasis in the cells. Working in concert with the ubiquitin proteasome system, p97 promotes the retrotranslocation from cellular organelles and/or degradation of misfolded proteins. Consequently, p97 inhibition has emerged as a novel therapeutic target in cancer cells, especially those that have a highly secretory phenotype. This review summarizes our current understanding of the function of p97 in maintaining protein homeostasis and its inhibition with small molecule inhibitors as an emerging strategy to target cancer cells.

Novel Carriers for Coenzyme Q10 Delivery.

BACKGROUND: Coenzyme Q10, a natural yellow benzoquinone, is a vitamin-like substance commonly found in blood and inner mitochondrial and cellular membranes. It is a natural antioxidant principle which plays an essential role in maintaining several biochemical pathways of body. It has exhibited many pharmacological activities in chronic heart failure, cardiofaciocutaneous syndrome, diabetes mellitus, carcinomas, autoimmune disease, cataract, asthma, periodontal disease and thyroid disorders. Moreover, it has demonstrated efficacy as nutritional supplement, in addition to its relevance in cosmetics. OBJECTIVE: Coenzyme Q10 is a potent molecule but its high molecular weight and low aqueous solubility hamper its use as a therapeutic agent. Therefore, various novel drug delivery systems have been explored and developed to overcome these limitations in literature. Hence, objective of this review is to summarize the recent works on design and development of novel drug delivery systems for CoQ10, which include liposomes, polymeric nanoparticles, polymeric micelles, solid lipid nanoparticles, nanostructured lipid carriers, self-emulsifying drug delivery systems, nanoemulsions, solid and aqueous dispersions. Further, an account of pharmaceutical studies has also been given. RESULTS & CONCLUSION: The reported studies indicate the promise of nanotechnology in enhancing the therapeutic value of CoQ10, promoting its usage as first line therapeutic agent, thus, revolutionizing its role in current medical therapy. The application of CoQ10 in pharmaceutical industry has grown tremendously in the past decade, due to its versatile nature. The successful application of this molecule in medicine, cosmetics and nutraceuticals points the way for its future development.

Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia.

CLL is a disease characterized by chromosomal deletions, acquired copy number changes and aneuploidy. Recent studies have shown that overexpression of Heat Shock Factor (HSF) 1 in aneuploid tumor cells can overcome deficiencies in heat shock protein (HSP) 90-mediated protein folding and restore protein homeostasis. Interestingly, several independent studies have demonstrated that HSF1 expression and activity also affects the chaperoning of HSP90 kinase clients, although the mechanism underlying this observation is unclear. Here, we determined how HSF1 regulates HSP90 function using CLL as a model system. We report that HSF1 is overexpressed in CLL and treatment with triptolide (a small molecule inhibitor of HSF1) induces apoptosis in cultured and primary CLL B-cells. We demonstrate that knockdown of HSF1 or its inhibition with triptolide results in the reduced association of HSP90 with its kinase co-chaperone cell division cycle 37 (CDC37), leading to the partial depletion of HSP90 client kinases, Bruton's Tyrosine Kinase (BTK), c-RAF and cyclin-dependent kinase 4 (CDK4). Treatment with triptolide or HSF1 knockdown disrupts the cytosolic complex between HSF1, p97, HSP90 and the HSP90 deacetylase- Histone deacetylase 6 (HDAC6). Consequently, HSF1 inhibition results in HSP90 acetylation and abrogation of its chaperone function. Finally, tail vein injection of Mec-1 cells into Rag2-/-IL2Rγc-/- mice followed by treatment with minnelide (a pro-drug of triptolide), reduced leukemia, increased survival and attenuated HSP90-dependent survival signaling in vivo. In conclusion, our study provides a strong rationale to target HSF1 and test the activity of minnelide against human CLL.

Heat shock factor 1 in protein homeostasis and oncogenic signal integration.

Heat shock factor 1 (HSF1) is a stress-inducible transcription factor and has been described as a multi-faceted modulator of tumorigenesis. Heat shock, accumulation of misfolded proteins, or malignant transformation promotes the activation and nuclear translocation of HSF1, where it binds to the promoters of heat shock proteins and an array of nonheat shock-regulated proteins to upregulate their transcription. These stress-responsive and tumor-promoting genes in turn alter the ability of tumor cells to respond to a variety of stresses and enable them to thrive in less than favorable growth conditions. Although a direct role for HSF1 in promoting mRNA transcription of tumor-promoting genes has been suggested, it appears that this property is context- and cell-type dependent. Furthermore, recent studies have demonstrated a direct involvement of mTOR signaling in regulating HSF1-mediated transcription, thus establishing a direct link between protein translation and HSF1 activity. Interestingly, there is a growing understanding of the signaling pathways that are modulated by HSF1 in a variety of tumor types and the co-option of these survival pathways by HSF1 to promote tumorigenesis. This review will focus on the role of HSF1 in protein homeostasis and HSF1-mediated oncogenic signaling pathways that together promote tumorigenesis.

Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL.