Publications by authors named "Charles R Ashby"

143 Publications

Alternative approaches to overcome chemoresistance to apoptosis in cancer.

Adv Protein Chem Struct Biol 2021 9;126:91-122. Epub 2021 Mar 9.

Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH, United States. Electronic address:

Apoptosis, or programmed cell death, is a form of regulated cell death (RCD) that is essential for organogenesis and homeostatic maintenance of normal cell populations. Apoptotic stimuli activate the intrinsic and/or extrinsic pathways to induce cell death due to perturbations in the intracellular and extracellular microenvironments, respectively. In patients with cancer, the induction of apoptosis by anticancer drugs and radiation can produce cancer cell death. However, tumor cells can adapt and become refractory to apoptosis-inducing therapies, resulting in the development of clinical resistance to apoptosis. Drug resistance facilitates the development of aggressive primary tumors that eventually metastasize, leading to therapy failure and mortality. To overcome the resistance to apoptosis to neoadjuvant chemotherapy or targeted therapy, alternative targets of RCD can be induced in apoptosis-resistant cancer cells. Alternatively, cell death can be independent of apoptosis and this strategy could be utilized to develop novel anti-cancer therapies. This chapter discusses approaches that could be employed to overcome clinical resistance to apoptosis in cancer cells.
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http://dx.doi.org/10.1016/bs.apcsb.2021.01.005DOI Listing
March 2021

From nicotine to the cholinergic anti-inflammatory reflex - Can nicotine alleviate the dysregulated inflammation in COVID-19?

J Immunotoxicol 2021 12;18(1):23-29

Department of Pharmaceutical Sciences, St. John's University, Queens, NY, USA.

The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.
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http://dx.doi.org/10.1080/1547691X.2021.1875085DOI Listing
December 2021

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach.

Front Cell Dev Biol 2021 4;9:649434. Epub 2021 Mar 4.

College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Chronic myelogenous leukemia (CML) typically results from a reciprocal translocation between chromosomes 9 and 22 to produce the oncogene that when translated, yields the p210 BCR-ABL protein in more than 90% of all CML patients. This protein has constitutive tyrosine kinase activity that activates numerous downstream pathways that ultimately produces uncontrolled myeloid proliferation. Although the use of the BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib have increased the overall survival of CML patients, their use is limited by drug resistance and severe adverse effects. Therefore, there is the need to develop novel compounds that can overcome these problems that limit the use of these drugs. Therefore, in this study, we sought to find novel compounds using Hypogen and Hiphip pharmacophore models based on the structures of clinically approved BCR-ABL TKIs. We also used optimal pharmacophore models such as three-dimensional queries to screen the ZINC database to search for potential BCR-ABL inhibitors. The hit compounds were further screened using Lipinski's rule of five, ADMET and molecular docking, and the efficacy of the hit compounds was evaluated. Our results indicated that compound ZINC21710815 significantly inhibited the proliferation of K562, BaF3/WT, and BaF3/T315I leukemia cells by inducing cell cycle arrest. The compound ZINC21710815 decreased the expression of p-BCR-ABL, STAT5, and Crkl and produced apoptosis and autophagy. Our results suggest that ZINC21710815 may be a potential BCR-ABL inhibitor that should undergo evaluation.
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http://dx.doi.org/10.3389/fcell.2021.649434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969810PMC
March 2021

Therapeutic strategies to overcome taxane resistance in cancer.

Drug Resist Updat 2021 Mar 27;55:100754. Epub 2021 Feb 27.

Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India. Electronic address:

One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. In vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and β-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients.
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http://dx.doi.org/10.1016/j.drup.2021.100754DOI Listing
March 2021

The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

The overexpression of ATP-binding cassette transporter, ABCG2, plays an important role in mediating multidrug resistance (MDR) in certain types of cancer cells. ABCG2-mediated MDR can significantly attenuate or abrogate the efficacy of anticancer drugs by increasing their efflux from cancer cells. In this study, we determined the efficacy of the novel benzamide derivative, VKNG-2, to overcome MDR due to the overexpression of the ABCG2 transporter in the colon cancer cell line, S1-M1-80. , 5 μM of VKNG-2 reversed the resistance of S1-M1-80 cell line to mitoxantrone (70-fold increase in efficacy) or SN-38 (112-fold increase in efficacy). In contrast, 5 μM of VKNG-2 did not significantly alter either the expression of ABCG2, AKT, and PI3K p110β protein or the subcellular localization of the ABCG2 protein compared to colon cancer cells incubated with the vehicle. Molecular docking data indicated that VKNG-2 had a high docking score (-10.2 kcal/mol) for the ABCG2 transporter substrate-drug binding site whereas it had a low affinity on ABCB1 and ABCC1 transporters. Finally, VKNG-2 produced a significant concentration-dependent increase in ATPase activity (EC = 2.3 µM). In conclusion, our study suggests that , VKNG-2 reverses the resistance of S1-M1-80, a cancer cell line resistant to mitoxantrone and SN-38, by inhibiting the efflux function of the ABCG2 transporter.
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http://dx.doi.org/10.3390/ijms22052463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957563PMC
February 2021

Gold nanoparticles: synthesis, physiochemical properties and therapeutic applications in cancer.

Drug Discov Today 2021 May 4;26(5):1284-1292. Epub 2021 Feb 4.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA. Electronic address:

Gold nanoparticles (AuNPs) have been shown to be useful as carriers of various anticancer drugs as well as diagnosis platforms. In this review, we discuss the synthesis and physiochemical properties of AuNPs. We also highlight the photothermal and photodynamic properties of AuNPs and relevant applications in therapeutic studies. Furthermore, we review the applications of AuNPs in cancer treatment as and their underlying anticancer mechanisms in multiple types of cancer.
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http://dx.doi.org/10.1016/j.drudis.2021.01.030DOI Listing
May 2021

The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages.

Antioxidants (Basel) 2021 Jan 19;10(1). Epub 2021 Jan 19.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.

Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary infections. This study reports that the activation of the α7 nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator, GAT107, decreases the bacterial burden in mouse lungs by improving hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with GAT107 (3.3 µM) rescues hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly, GAT107 (3.3 µM) also attenuated oxidative stress in hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (F-actin) from oxidation. Furthermore, GAT107 (3.3 µM) increases the (1) activity of superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of heme oxygenase-1 (HO-1) in macrophages exposed to hyperoxia. Overall, these data suggest that the novel α7nAChR compound, GAT107, could be used to improve host defense functions in patients, such as those with COVID-19, who are exposed to prolonged periods of hyperoxia.
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http://dx.doi.org/10.3390/antiox10010135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835977PMC
January 2021

The use of zebrafish model in prostate cancer therapeutic development and discovery.

Cancer Chemother Pharmacol 2021 03 3;87(3):311-325. Epub 2021 Jan 3.

Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH, USA.

Zebrafish is now among the leading in vivo model for cancer research, including prostate cancer. They are an alternative economic model being used to study cancer development, proliferation, and metastasis. They can also be effectively utilized for the development of cancer drugs at all levels, including target validation, and high-throughput screening for possible lead molecules. In this review, we provide a comprehensive overview of the role of zebrafish as an in vivo model in prostate cancer research. Globally, prostate cancer is a leading cause of death in men. Although many molecular mechanisms have been identified as playing a role in the pathogenesis of prostate cancer, there is still a significant need to understand the initial events of the disease. Furthermore, current treatments are limited by the emergence of severe toxicities and multidrug resistance. There is an essential need for economical and relevant research tools to improve our understanding and overcome these problems. This review provides a comprehensive summary of studies that utilized zebrafish for different aims in prostate cancer research. We discuss the use of zebrafish in prostate cancer cell proliferation and metastasis, defining signaling pathways, drug discovery and therapeutic development against prostate cancer, and toxicity studies. Finally, this review highlights limitations in this field and future directions to efficiently use zebrafish as a robust model for prostate cancer therapeutics development.
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http://dx.doi.org/10.1007/s00280-020-04211-zDOI Listing
March 2021

Retraction Note: The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.

Mol Med 2020 Dec 30;26(1):132. Epub 2020 Dec 30.

Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Allied Health Professions, Health Sciences, 128 St. Albert Hall, 8000 Utopia Parkway, Queens, NY, 11439, USA.

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http://dx.doi.org/10.1186/s10020-020-00265-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772916PMC
December 2020

Doxycycline for ESBL-E cystitis.

Clin Infect Dis 2020 Dec 29. Epub 2020 Dec 29.

Department of Family Medicine; University Medical Center, Lubbock, TX.

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http://dx.doi.org/10.1093/cid/ciaa1898DOI Listing
December 2020

Sapitinib Reverses Anticancer Drug Resistance in Colon Cancer Cells Overexpressing the ABCB1 Transporter.

Front Oncol 2020 9;10:574861. Epub 2020 Oct 9.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

The efficacy of anti-cancer drugs in patients can be attenuated by the development of multi-drug resistance (MDR) due to ATP-binding cassette (ABC) transporters overexpression. In this study, we determined the reversal efficacy of the epidermal growth factor receptor (EFGR) inhibitor, saptinib, in SW620 and SW720/Ad300 colon cancer cells and HEK293/ABCB1 cells which overexpress the ABCB1 transporter. Sapitinib significantly increased the efficacy of paclitaxel and doxorubicin in ABCB1 overexpressing cells without altering the expression or the subcellular location of the ABCB1 transporter. Sapitinib significantly increased the accumulation of [H]-paclitaxel in SW620/AD300 cells probably by stimulating ATPase activity which could competitively inhibit the uptake of [H]-paclitaxel. Furthermore, sapitinib inhibited the growth of resistant multicellular tumor spheroids (MCTS). The docking study indicated that sapitinib interacted with the efflux site of ABCB1 transporter by π-π interaction and two hydrogen bonds. In conclusion, our study suggests that sapitinib surmounts MDR mediated by ABCB1 transporter in cancer cells.
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http://dx.doi.org/10.3389/fonc.2020.574861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581728PMC
October 2020

Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Currently, chemotherapy is a first-line treatment for CRC. However, one major drawback of chemotherapy is the emergence of multidrug resistance (MDR). It has been well-established that the overexpression of the ABCB1 and/or ABCG2 transporters can produce MDR in cancer cells. In this study, we report that in vitro, poziotinib can antagonize both ABCB1- and ABCG2-mediated MDR at 0.1-0.6 μM in the human colon cancer cell lines, SW620/Ad300 and S1-M1-80. Mechanistic studies indicated that poziotinib increases the intracellular accumulation of the ABCB1 transporter substrates, paclitaxel and doxorubicin, and the ABCG2 transporter substrates, mitoxantrone and SN-38, by inhibiting their substrate efflux function. Accumulation assay results suggested that poziotinib binds reversibly to the ABCG2 and ABCB1 transporter. Furthermore, western blot experiments indicated that poziotinib, at 0.6 μM, significantly downregulates the expression of the ABCG2 but not the ABCB1 transporter protein, suggesting that the ABCG2 reversal effect produced by poziotinib is due to transporter downregulation and inhibition of substrate efflux. Poziotinib concentration-dependently stimulated the ATPase activity of both ABCB1 and ABCG2, with EC values of 0.02 μM and 0.21 μM, respectively, suggesting that it interacts with the drug-substrate binding site. Molecular docking analysis indicated that poziotinib binds to the ABCB1 (-6.6 kcal/mol) and ABCG2 (-10.1 kcal/mol) drug-substrate binding site. In summary, our novel results show that poziotinib interacts with the ABCB1 and ABCG2 transporter, suggesting that poziotinib may increase the efficacy of certain chemotherapeutic drugs used in treating MDR CRC.
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http://dx.doi.org/10.3390/cancers12113249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694178PMC
November 2020

The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.

Mol Med 2020 10 30;26(1):98. Epub 2020 Oct 30.

Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.

Background: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia.

Method: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O) and subsequently challenged with PA.

Results: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA.

Conclusions: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.
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http://dx.doi.org/10.1186/s10020-020-00224-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596622PMC
October 2020

Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp).

Med Res Rev 2021 01 12;41(1):525-555. Epub 2020 Oct 12.

Key Laboratory of Advanced Drug Preparation Technologies, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.

Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP-binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P-glycoprotein (P-gp/ABCB1) has been most well-established. The clinical co-administration of P-gp drug efflux inhibitors, in combination with anticancer drugs which are P-gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P-gp-mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P-gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure-activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P-gp inhibitors in the past 5 years. The development of P-gp inhibitors will increase our knowledge of the mechanisms and functions of P-gp-mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P-gp transporter overexpression has been implicated in MDR.
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http://dx.doi.org/10.1002/med.21739DOI Listing
January 2021

Characterization of a novel HDAC/RXR/HtrA1 signaling axis as a novel target to overcome cisplatin resistance in human non-small cell lung cancer.

Mol Cancer 2020 09 2;19(1):134. Epub 2020 Sep 2.

Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.

Background: Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance.

Methods: A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway.

Results: HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis.

Conclusion: Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.
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http://dx.doi.org/10.1186/s12943-020-01256-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466461PMC
September 2020

Methyl-Cantharidimide (MCA) Has Anticancer Efficacy in ABCB1- and ABCG2-Overexpressing and Cisplatin Resistant Cancer Cells.

Front Oncol 2020 26;10:932. Epub 2020 Jun 26.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

In this study, we investigated the efficacy of methyl-cantharidimide (MCA), a cantharidin (CTD) analog, as an anticancer drug, in cancer cells overexpressing either ABCB1 or ABCG2 transporters and in cisplatin-resistant cancer cells. The results indicated that: (i) MCA was efficacious in the ABCB1-overexpressing cell line, KB-C2, and the ABCB1-gene-transfected cell line, HEK293/ABCB1 (IC50 from 6.37 to 8.44 mM); (ii) MCA was also efficacious in the ABCG2-overexpressing cell line, NCI-H460/MX20, and the ABCG2-gene-transfected cell lines, HEK293/ABCG2-482-R2, HEK293/ABCG2-482-G2, and the HEK293/ABCG2-482-T7 cell lines (IC50 from 6.37 to 9.70 mM); (iii) MCA was efficacious in the cisplatin resistant cancer cell lines, KCP-4 and BEL-7404/CP20 (IC50 values from 7.05 to 8.16 mM); (iv) MCA (up to 16 mM) induced apoptosis in both BEL-7404 and BEL-7404/CP20 cancer cells; (v) MCA arrested both BEL-7404 and BEL-7404/CP20 cancer cells in the G0/G1 phase of the cell cycle; (vi) MCA (8 mM) upregulated the expression level of the protein, unc-5 netrin receptor B (UNC5B) in HepG2 and BEL-7404 cancer cells. Overall, our results indicated that MCA's efficacy in ABCB1- and ABCG2-overexpressing and cisplatin resistant cancer cells is due to the induction of apoptosis and cell cycle arrest in the G0/G1 phase.
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http://dx.doi.org/10.3389/fonc.2020.00932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333678PMC
June 2020

Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation.

Molecules 2020 Jul 4;25(13). Epub 2020 Jul 4.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.

New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (-), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial cells (HMECs). Two compounds, and , had the highest efficacy and selectivity towards MDA-MB-231 cells, and thus, were further evaluated by mechanistic experiments. The results indicated that both compounds and induced apoptosis by (1) inducing cell cycle arrest at the G2 phase in MDA-MB-231 cells, and (2) activating the intrinsic apoptotic pathways in a concentration-dependent manner. Physicochemical characterizations of these compounds suggested that they can be further optimized as potential anticancer compounds for TNBC cells. Overall, our results suggest that and could be suitable leads for developing novel compounds to treat TNBC.
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http://dx.doi.org/10.3390/molecules25133063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412250PMC
July 2020

Edaravone: A potential treatment for the COVID-19-induced inflammatory syndrome?

Pharmacol Res 2020 10 30;160:105055. Epub 2020 Jun 30.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States. Electronic address:

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http://dx.doi.org/10.1016/j.phrs.2020.105055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326414PMC
October 2020

The α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuates hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation.

Mol Med 2020 06 29;26(1):63. Epub 2020 Jun 29.

Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.

Background: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury.

Methods: Mice were exposed to hyperoxia (≥99% O) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline.

Results: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology.

Conclusions: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.
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http://dx.doi.org/10.1186/s10020-020-00177-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322715PMC
June 2020

Potential Use of Sofosbuvir in the Prophylaxis for Rabies.

Front Pharmacol 2020 8;11:472. Epub 2020 Apr 8.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

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http://dx.doi.org/10.3389/fphar.2020.00472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156619PMC
April 2020

Plasminogen activator inhibitor (PAI) trap3, an exocellular peptide inhibitor of PAI-1, attenuates the rearrangement of F-actin and migration of cancer cells.

Exp Cell Res 2020 06 30;391(1):111987. Epub 2020 Mar 30.

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Background: The protein plasminogen activator inhibitor-1 (PAI-1), an inhibitor specific for urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), has been shown to have a key role in cancer metastases. Currently, it is unknown as to whether the exocellular inhibition of PAI-1 can inhibit the migration of cancer cells.

Methods: By fusing the mutated serine protease domain (SPD) of uPA and human serum albumin (HSA), PAItrap3, a protein that traps PAI-1, was synthesized and experiments were conducted to determine if exocellular PAItrap3 attenuates PAI-1-induced cancer cell migration in vitro.

Results: PAItrap3 (0.8 μM) significantly inhibited the motility of MCF-7, MDA-MB-231, HeLa and 4T1 cancer cells, by 90%, 50%, 30% and 20%, respectively, without significantly altering their proliferation. The PAI-1-induced rearrangement of F-actin was significantly inhibited by PAItrap3, which produced a decrease in the number of cell protrusions by at least 20%.

Conclusions: In vitro, PAItrap3 inhibited PAI-1-induced cancer cell migration, mainly through inhibiting the rearrangement of F-actin. Overall, these results, provided they can be extrapolated to humans, suggest that the PAItrap3 protein could be used as an exocellular inhibitor to attenuate cancer metastases.
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http://dx.doi.org/10.1016/j.yexcr.2020.111987DOI Listing
June 2020

Long non-coding RNAs regulate drug resistance in cancer.

Mol Cancer 2020 03 12;19(1):54. Epub 2020 Mar 12.

College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY, 11439, USA.

Chemoresistance, whether intrinsic or acquired, is a major obstacle in the treatment of cancer. The resistance of cancer cells to chemotherapeutic drugs can result from various mechanisms. Over the last decade, it has been reported that 1ong noncoding RNAs (lncRNAs) can mediate carcinogenesis and drug resistance/sensitivity in cancer cells. This article reviews, in detail, recent studies regarding the roles of lncRNAs in mediating drug resistance.
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http://dx.doi.org/10.1186/s12943-020-01162-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066752PMC
March 2020

Lipid-Saporin Nanoparticles for the Intracellular Delivery of Cytotoxic Protein to Overcome ABC Transporter-Mediated Multidrug Resistance In Vitro and In Vivo.

Cancers (Basel) 2020 Feb 21;12(2). Epub 2020 Feb 21.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

Although the judicious use of anticancer drugs that target one or more receptor tyrosine kinases constitutes an effective strategy to attenuate tumor growth, drug resistance is commonly encountered in cancer patients. The ATP-binding cassette transporters are one of the major contributors to the development of multidrug resistance as their overexpression significantly decreases the intracellular concentration and thus, the efficacy of certain anticancer drugs. Therefore, the development of treatment strategies that would not be susceptible to efflux or excretion by specific ABC transporters could overcome resistance to treatment. Here, we investigated the anticancer efficacy of saporin, a ribosome-inactivating protein. Since saporin has poor permeability across the cell membrane, it was encapsulated in a lipid-based nanoparticle system (EC16-1) that effectively delivered the formulation (EC16-1/saporin) intracellularly and produced anti-cancer efficacy. EC16-1/saporin, at nanomolar concentrations, significantly inhibited the cellular proliferation of parental and ABCB1- and ABCG2-overexpressing cancer cells. EC16-1/saporin did not significantly alter the subcellular localization of ABCB1 and ABCG2. In addition, EC16-1/saporin induced apoptosis in parental and ABCB1- and ABCG2-overexpressing cancer cells. In a murine model system, EC16-1/saporin significantly inhibited the tumor growth in mice xenografted with parental and ABCB1- and ABCG2-overexpressing cancer cells. Our findings suggest that the EC16-1/saporin combination could potentially be a novel therapeutic treatment in patients with parental or ABCB1- and ABCG2-positive drug-resistant cancers.
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http://dx.doi.org/10.3390/cancers12020498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072609PMC
February 2020

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1.

Int J Mol Sci 2020 02 1;21(3). Epub 2020 Feb 1.

Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University Queens, Queens, NY 11439, USA.

Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI). Using both ascorbic acid (AA, also known as vitamin C) and sulforaphane (SFN), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), we tested the hypothesis that dietary antioxidants can mitigate HALI by ameliorating HMGB1-compromised macrophage function in phagocytosis by attenuating hyperoxia-induced extracellular HMGB1 accumulation. Our results indicated that SFN, which has been shown to attenute HALI in mice exposed to hyperoxia, dose-dependently restored hyperoxia-compromised macrophage function in phagocytosis (75.9 ± 3.5% in 0.33 µM SFN versus 50.7 ± 1.8% in dimethyl sulfoxide (DMSO) control, p < 0.05) by reducing oxidative stress and HMGB1 release from cultured macrophages (47.7 ± 14.7% in 0.33 µM SFN versus 93.1 ± 14.6% in DMSO control, < 0.05). Previously, we have shown that AA enhances hyperoxic macrophage functions by reducing hyperoxia-induced HMGB1 release. Using a mouse model of HALI, we determined the effects of AA on hyperoxia-induced inflammatory lung injury. The administration of 50 mg/kg of AA to mice exposed to 72 h of ≥98% O significantly decreased hyperoxia-induced oxidative and nitrosative stress in mouse lungs. There was a significant decrease in the levels of airway HMGB1 (43.3 ± 12.2% in 50 mg/kg AA versus 96.7 ± 9.39% in hyperoxic control, < 0.05), leukocyte infiltration (60.39 ± 4.137% leukocytes numbers in 50 mg/kg AA versus 100 ± 5.82% in hyperoxic control, < 0.05) and improved lung integrity in mice treated with AA. Our study is the first to report that the dietary antioxidants, ascorbic acid and sulforaphane, ameliorate HALI and attenuate hyperoxia-induced macrophage dysfunction through an HMGB1-mediated pathway. Thus, dietary antioxidants could be used as potential treatments for oxidative-stress-induced acute inflammatory lung injury in patients receiving mechanical ventilation.
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http://dx.doi.org/10.3390/ijms21030977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037000PMC
February 2020

Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update.

Drug Resist Updat 2020 03 22;49:100681. Epub 2020 Jan 22.

Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310022, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China. Electronic address:

The presence of multidrug resistance (MDR) in malignant tumors is one of the primary causes of treatment failure in cancer chemotherapy. The overexpression of the ATP binding cassette (ABC) transporter, P-glycoprotein (P-gp), which significantly increases the efflux of certain anticancer drugs from tumor cells, produces MDR. Therefore, inhibition of P-gp may represent a viable therapeutic strategy to overcome cancer MDR. Over the past 4 decades, many compounds with P-gp inhibitory efficacy (referred to as first- and second-generation P-gp inhibitors) have been identified or synthesized. However, these compounds were not successful in clinical trials due to a lack of efficacy and/or untoward toxicity. Subsequently, third- and fourth-generation P-gp inhibitors were developed but dedicated clinical trials did not indicate a significant therapeutic effect. In recent years, an extraordinary array of highly potent, selective, and low-toxicity P-gp inhibitors have been reported. Herein, we provide a comprehensive review of the synthetic and natural products that have specific inhibitory activity on P-gp drug efflux as well as promising chemosensitizing efficacy in MDR cancer cells. The present review focuses primarily on the structural features, design strategies, and structure-activity relationships (SAR) of these compounds.
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http://dx.doi.org/10.1016/j.drup.2020.100681DOI Listing
March 2020

Expression of Concern to: The α7 nicotine acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.

Mol Med 2020 02 3;26(1):16. Epub 2020 Feb 3.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA.

The Editors-in-Chief would like to alert readers that this article (Sitapara et al. 2014) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.
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http://dx.doi.org/10.1186/s10020-020-0143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998071PMC
February 2020

Flavonoids as Multi-Target Compounds: A Special Emphasis on their Potential as Chemo-adjuvants in Cancer Therapy.

Curr Pharm Des 2020 ;26(15):1712-1728

Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH 43606, United States.

Flavonoids are low molecular weight, polyphenolic phytochemicals, obtained from secondary metabolism of various plant compounds. They have a spectrum of pharmacological efficacies, including potential anticancer efficacy. Natural flavonoids are present in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. Flavonoids can attenuate or inhibit the initiation, promotion and progression of cancer by modulating various enzymes and receptors in diverse pathways that involve cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis. Furthermore, in vitro, flavonoids have been shown to reverse multidrug resistance when used as chemo-adjuvants. Flavonoids (both natural and synthetic analogues) interact with several oncogenic targets through dependent and independent mechanisms to mediate their anticancer efficacy in different types of cancer cells.
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http://dx.doi.org/10.2174/1381612826666200128095248DOI Listing
November 2020

The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.

Biochem Pharmacol 2020 06 20;176:113817. Epub 2020 Jan 20.

Department of Pharmaceutical Sciences, St. John's University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA; Cardiopulmonary Research, The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY 11030, USA. Electronic address:

Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize Pseudomonas aeruginosa (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM-800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.
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http://dx.doi.org/10.1016/j.bcp.2020.113817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402419PMC
June 2020

A vaginal nanoformulation of a SphK inhibitor attenuates lipopolysaccharide-induced preterm birth in mice.

Nanomedicine (Lond) 2019 11 15;14(21):2835-2851. Epub 2019 Nov 15.

Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St John's University, Queens, NY 11439, USA.

Previously, we have shown that inhibition of SphK by the SphK inhibitor-II (SKI II) prevents lipopolysaccharide-induced preterm birth in mice. The aim of this study was to develop a vaginal self-nanoemulsifying drug-delivery system (SNEDDS) for SKI II. A SKI II-loaded SNEDDS was characterized and tested in a murine preterm birth model. The SNEDDS immediately formed a gel and then slowly emulsified to nanoglobules with over 500-fold enhancement of SKI II solubility at vaginal pH. Intravaginal administration of the SKI II SNEDDS significantly decreased lipopolysaccharide-induced preterm birth in mice. A vaginal nanoformulation of SKI II represents a novel, noninvasive approach to prevent preterm birth.
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http://dx.doi.org/10.2217/nnm-2019-0243DOI Listing
November 2019

Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance.

Drug Resist Updat 2020 01 11;48:100663. Epub 2019 Nov 11.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address:

Drug resistance is a major obstacle in the field of pre-clinical and clinical therapeutics. The development of novel technologies and targeted therapies have yielded new modalities to overcome drug resistance, but multidrug resistance (MDR) remains one of the major challenges in the treatment of cancer. The ubiquitin-proteasome system (UPS) has a central role in regulating the levels and activities of a multitude of proteins as well as regulation of cell cycle, gene expression, response to oxidative stress, cell survival, cell proliferation and apoptosis. Therefore, inhibition of the UPS could represent a novel strategy for the treatment and overcoming of drug resistance in chemoresistant malignancies. In 2003, bortezomib was approved by the FDA for the treatment of multiple myeloma (MM). However, due to its limitations, second generation proteasome inhibitors (PIs) like carfilzomib, ixazomib, oprozomib, delanzomib and marizomib were introduced which displayed clinical activity in bortezomib-resistant tumors. Past studies have demonstrated that proteasome inhibition potentiates the anti-cancer efficacy of other chemotherapeutic drugs by: i) decreasing the expression of anti-apoptotic proteins such as TNF-α and NF-kB, ii) increasing the levels of Noxa, a pro-apoptotic protein, iii) activating caspases and inducing apoptosis, iv) degrading the pro-survival protein, induced myeloid leukemia cell differentiation protein (MCL1), and v) inhibiting drug efflux transporters. In addition, the mechanism of action of the immunoproteasome inhibitors, ONX-0914 and LU-102, suggested their therapeutic role in the combination treatment with PIs. In the current review, we discuss various PIs and their underlying mechanisms in surmounting anti-tumor drug resistance when used in combination with conventional chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.drup.2019.100663DOI Listing
January 2020