Publications by authors named "Amit K Tiwari"

85 Publications

Biomimetic Microfluidic Platforms for the Assessment of Breast Cancer Metastasis.

Front Bioeng Biotechnol 2021 11;9:633671. Epub 2021 Mar 11.

Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States.

Of around half a million women dying of breast cancer each year, more than 90% die due to metastasis. Models necessary to understand the metastatic process, particularly breast cancer cell extravasation and colonization, are currently limited and urgently needed to develop therapeutic interventions necessary to prevent breast cancer metastasis. Microfluidic approaches aim to reconstitute functional units of organs that cannot be modeled easily in traditional cell culture or animal studies by reproducing vascular networks and parenchyma on a chip in a three-dimensional, physiologically relevant system. In recent years, microfluidics models utilizing innovative biomaterials and micro-engineering technologies have shown great potential in our effort of mechanistic understanding of the breast cancer metastasis cascade by providing 3D constructs that can mimic cellular microenvironment and the ability to visualize and monitor cellular interactions in real-time. In this review, we will provide readers with a detailed discussion on the application of the most up-to-date, state-of-the-art microfluidics-based breast cancer models, with a special focus on their application in the engineering approaches to recapitulate the metastasis process, including invasion, intravasation, extravasation, breast cancer metastasis organotropism, and metastasis niche formation.
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http://dx.doi.org/10.3389/fbioe.2021.633671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992012PMC
March 2021

Resveratrol-loaded nanomedicines for cancer applications.

Cancer Rep (Hoboken) 2021 Mar 2:e1353. Epub 2021 Mar 2.

Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.

Background: Resveratrol (3, 5, 4 -trihydroxystilbene), a natural polyphenol and phytoalexin, has drawn considerable attention in the past decade due to its wide variety of therapeutic activities such as anticancer, anti-inflammatory, and antioxidant properties. However, its poor water solubility, low chemical stability, and short biological half-life limit its clinical utility.

Recent Findings: Nanoparticles overcome the limitations associated with conventional chemotherapeutic drugs, such as limited availability of drugs to the tumor tissues, high systemic exposures, and consequent toxicity to healthy tissues. This review focuses on the physicochemical properties of resveratrol, the therapeutic potential of resveratrol nano-formulations, and the anticancer activity of resveratrol encapsulated nanoparticles on various malignancies such as skin, breast, prostate, colon, liver, ovarian, and lung cancers (focusing on both in vitro and in vivo studies).

Conclusions: Nanotechnology approaches have been extensively utilized to achieve higher solubility, improved oral bioavailability, enhanced stability, and controlled release of resveratrol. The resveratrol nanoparticles have markedly enhanced its anticancer activity both in vitro and in vivo, thus considering it as a potential strategy to fight various cancers.
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http://dx.doi.org/10.1002/cnr2.1353DOI Listing
March 2021

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

Cancer Chemother Pharmacol 2021 Mar 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

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

AAPS PharmSciTech 2020 Nov 4;21(8):304. Epub 2020 Nov 4.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA.

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.
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http://dx.doi.org/10.1208/s12249-020-01846-2DOI Listing
November 2020

Evaluation of Cytotoxicity and Taste-Masking Effect of Selected Flavors on Dental Lidocaine HCl Injection.

Pharmaceuticals (Basel) 2020 Oct 29;13(11). Epub 2020 Oct 29.

Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA.

Aim: Anxiety and intolerance to dental local anesthetic injections are common in patients undergoing dental procedures. This work was designed to study cytotoxicity of selected flavors in primary gingival keratinocytes (PGK), to acquire information on their suitability for use in dental lidocaine hydrochloride (LID) injection. We also evaluated the bio-mimetic taste of LID dental injection in the presence of selected flavors and sweetener using an Astree electronic tongue (ETongue).

Methods: The cytotoxicity of chocolate natural and artificial flavor (CTE), raspberry flavor artificial (RAS), cherry flavor (CHR), bitterness suppressor flavor (BSF) and lemon flavor extract (LFE) at various dilutions (0.16-10% /) was carried out in PGK using the live cell morphological analysis and MTT cell cytotoxicity assay. Based on the cytotoxicity data, CTE and RAS were added to Xylocaine (2%) along with 0.09% sodium saccharin and taste was assessed using an ETongue.

Results: After three hours of treatment, a dose-dependent cell death was induced by all flavors compared to the untreated control. BSF was found to be more toxic when compared to other flavors. CTE was found to be less toxic. The mean IC50 values of CTE, RAS, CHR, BSF and LFE in PGK were found to be 9.54, 8.43, 2.21, 0.38 and 4.01 mg/mL. Taste analysis with the ETongue showed a clear taste difference between the control and test formulations containing CTE and RAS flavors along with sodium saccharin.

Conclusion: CTE and RAS flavors in combination with 0.09% sodium saccharin can achieve a significant taste-masking effect in the dental LID injection.
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http://dx.doi.org/10.3390/ph13110353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693877PMC
October 2020

Role of eIF4A1 in triple-negative breast cancer stem-like cell-mediated drug resistance.

Cancer Rep (Hoboken) 2020 Oct 14:e1299. Epub 2020 Oct 14.

Department of Pharmacology & Experimental Therapeutics, University of Toledo Health Science Campus, Toledo, Ohio, USA.

In cap-dependent translation, the eukaryotic translation initiation factor 4A (eIF4A1) is an mRNA helicase is involved in unwinding of the secondary structure, such as the stem-loops, at the 5'-leader regions of the key oncogenic mRNAs. This facilitates ribosomal scanning and translation of the oncogenic mRNAs. eIF4A1 has a regulatory role in translating many oncoproteins that have vital roles in several steps of metastases. Sridharan et. al. have discovered and provide a novel insight into how eIF4A1 can play a regulatory role in drug resistance by influencing the levels of pluripotent Yamanaka transcription factors and ATP-binding cassette (ABC) transporters in triple-negative breast cancer (TNBC) stem-like cells. These findings may help us understand the molecular underpinnings of chemoresistance, especially in established metastases in TNBC. Importantly, eIF4A1 may form a novel clinical target in metastatic TNBC and the drug eFT226 from Effector Therapeutics targeting eIF4A1 is already in phase1-2 clinical trial.
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http://dx.doi.org/10.1002/cnr2.1299DOI Listing
October 2020

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

Department of Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA.

The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG) motif, which confers eIF4A dependency, was incorporated into the 5'-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients.
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http://dx.doi.org/10.3390/cancers12082169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465665PMC
August 2020

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes.

J Med Chem 2020 11 4;63(21):12290-12358. Epub 2020 Aug 4.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, p, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666045PMC
November 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

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

Editorial: The Role of Breast Cancer Stem Cells in Clinical Outcomes.

Front Oncol 2020 10;10:299. Epub 2020 Mar 10.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.

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http://dx.doi.org/10.3389/fonc.2020.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076080PMC
March 2020

Alternatives to Biological Skin in Permeation Studies: Current Trends and Possibilities.

Pharmaceutics 2020 Feb 13;12(2). Epub 2020 Feb 13.

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

The transdermal route of drugs has received increased attention in recent years due to numerous advantages over the oral and injectable routes, such as avoidance of the hepatic metabolism, protection of drugs from the gastrointestinal tract, sustained drug delivery, and good patient compliance. The assessment of ex vivo permeation during the pharmaceutical development process helps in understanding the product quality and performance of a transdermal delivery system. Generally, excised human skin relevant to the application site or animal skin is recommended for ex vivo permeation studies. However, the limited availability of the human skin and ethical issues surrounding the use of animal skin rendered these models less attractive in the permeation study. In the last three decades, enormous efforts have been put into developing artificial membranes and 3D cultured human skin models as surrogates to the human skin. This manuscript provides an insight on the European Medicines Agency (EMA) guidelines for permeation studies and the parameters affected when using Franz diffusion cells in the permeation study. The need and possibilities for skin alternatives, such as artificially cultured human skin models, parallel artificial membrane permeability assays (PAMPA), and artificial membranes for penetration and permeation studies, are comprehensively discussed.
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http://dx.doi.org/10.3390/pharmaceutics12020152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076422PMC
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

Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness.

Front Oncol 2019 6;9:1311. Epub 2019 Dec 6.

Department of Cancer Biology, University of Toledo Health Science Campus, Toledo, OH, United States.

Breast cancer stem cells (BCSCs) are intrinsically chemoresistant and capable of self-renewal. Following chemotherapy, patients can develop minimal residual disease due to BCSCs which can repopulate into a relapsed tumor. Therefore, it is imperative to co-target BCSCs along with the bulk tumor cells to achieve therapeutic success and prevent recurrence. So, it is vital to identify actionable molecular targets against both BCSCs and bulk tumor cells. Previous findings from our lab and others have demonstrated that inhibition of the emerging drug target eIF4A with Rocaglamide A (RocA) was efficacious against triple-negative breast cancer cells (TNBC). RocA specifically targets the pool of eIF4A bound to the oncogenic mRNAs that requires its helicase activity for their translation. This property enables specific targeting of tumor cells. The efficacy of RocA against BCSCs is unknown. In this study, we postulated that eIF4A could be a vulnerable node in BCSCs. In order to test this, we generated a paclitaxel-resistant TNBC cell line which demonstrated an elevated level of eIF4A along with increased levels of cancer stemness markers (ALDH activity and CD44), pluripotency transcription factors (SOX2, OCT4, and NANOG) and drug transporters (ABCB1, ABCG2, and ABCC1). Furthermore, genetic ablation of eIF4A resulted in reduced expression of ALDH1A1, pluripotency transcription factors and drug transporters. This pointed out that eIF4A is likely associated with selected set of proteins that are critical to BCSCs, and hence targeting eIF4A may eliminate BCSCs. Therefore, we isolated BCSCs from two TNBC cell lines: MDA-Bone-Un and SUM-159PT. Following RocA treatment, the self-renewal ability of the BCSCs was significantly reduced as determined by the efficiency of the formation of primary and secondary mammospheres. This was accompanied by a reduction in the levels of NANOG, OCT4, and drug transporters. Exposure to RocA also induced cell death of the BCSCs as evaluated by DRAQ7 and cell viability assays. RocA treatment induced apoptosis with increased levels of cleaved caspase-3. Overall, we identified that RocA is effective in targeting BCSCs, and eIF4A is an actionable molecular target in both BCSCs and bulk tumor cells. Therefore, anti-eIF4A inhibitors could potentially be combined synergistically with existing chemo-, radio- and/or immunotherapies.
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http://dx.doi.org/10.3389/fonc.2019.01311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909344PMC
December 2019

CCR5 and responses to cocaine: Addiction is not just about the brain.

Brain Behav Immun 2020 02 13;84:8-9. Epub 2019 Dec 13.

Department of Pharmacology & Experimental Therapeutics, University of Toledo, Toledo, OH, USA.

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http://dx.doi.org/10.1016/j.bbi.2019.12.008DOI Listing
February 2020

Stability-indicating HPLC method for acyclovir and lidocaine in topical formulations.

Biomed Chromatogr 2020 Mar 12;34(3):e4751. Epub 2020 Jan 12.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

A simple, rapid and accurate stability-indicating HPLC assay was developed for the determination of acyclovir and lidocaine in topical formulations. Chromatographic separation of acyclovir and lidocaine was achieved using a reversed-phase C column and a gradient mobile phase (20 mm ammonium acetate pH 3.5 in water and acetonitrile). The degradation products of acyclovir and lidocaine in the samples were analyzed by ultra performance liquid chromatography-time of flight mass spectrometry. The HPLC method successfully resolved the analytes from the impurities and degradation products in the topical formulation. Furthermore, the method detected the analytes from the human skin leachables following the extraction of the analytes in the skin homogenate samples. The method showed linearity over wide ranges of 5-500 and 10-200 μg/ml for acyclovir and lidocaine in the topical product, respectively, with a correlation coefficient (r ) >0.9995. The relative standard deviations for precision, repeatability, and robustness of the method validation assays were <2%. The skin extraction efficiency for acyclovir and lidocaine was 92.8 ± 0.7% and 91.3 ± 3.2%, respectively, with no interference from the skin leachables. Thus, simultaneous quantification of acyclovir and lidocaine in the topical formulations was achieved.
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http://dx.doi.org/10.1002/bmc.4751DOI Listing
March 2020

Novel and Alternative Targets Against Breast Cancer Stemness to Combat Chemoresistance.

Front Oncol 2019 16;9:1003. Epub 2019 Oct 16.

Department of Cancer Biology, University of Toledo, Toledo, OH, United States.

Breast cancer stem cells (BCSCs) play a vital role in tumor progression and metastasis. They are heterogeneous and inherently radio- and chemoresistant. They have the ability to self-renew and differentiate into non-BCSCs. These determinants of BCSCs including the plasticity between the mesenchymal and epithelial phenotypes often leads to minimal residual disease (MRD), tumor relapse, and therapy failure. By studying the resistance mechanisms in BCSCs, a combinatorial therapy can be formulated to co-target BCSCs and bulk tumor cells. This review addresses breast cancer stemness and molecular underpinnings of how the cancer stemness can lead to pharmacological resistance. This might occur through rewiring of signaling pathways and modulated expression of various targets that support survival and self-renewal, clonogenicity, and multi-lineage differentiation into heterogeneous bulk tumor cells following chemotherapy. We explore emerging novel and alternative molecular targets against BC stemness and chemoresistance involving survival, drug efflux, metabolism, proliferation, cell migration, invasion, and metastasis. Strategic targeting of such vulnerabilities in BCSCs may overcome the chemoresistance and increase the longevity of the metastatic breast cancer patients.
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http://dx.doi.org/10.3389/fonc.2019.01003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805781PMC
October 2019

ABC Transporter-Mediated Multidrug-Resistant Cancer.

Adv Exp Med Biol 2019 ;1141:549-580

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

ATP-binding cassette (ABC) transporters are involved in active pumping of many diverse substrates through the cellular membrane. The transport mediated by these proteins modulates the pharmacokinetics of many drugs and xenobiotics. These transporters are involved in the pathogenesis of several human diseases. The overexpression of certain transporters by cancer cells has been identified as a key factor in the development of resistance to chemotherapeutic agents. In this chapter, the localization of ABC transporters in the human body, their physiological roles, and their roles in the development of multidrug resistance (MDR) are reviewed. Specifically, P-glycoprotein (P-GP), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP/ABCG2) are described in more detail. The potential of ABC transporters as therapeutic targets to overcome MDR and strategies for this purpose are discussed as well as various explanations for the lack of efficacy of ABC drug transporter inhibitors to increase the efficiency of chemotherapy.
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http://dx.doi.org/10.1007/978-981-13-7647-4_12DOI Listing
October 2019

Role of Ceramides in Drug Delivery.

AAPS PharmSciTech 2019 Aug 13;20(7):287. Epub 2019 Aug 13.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA.

Ceramides belong to the sphingolipid group of lipids, which serve as both intracellular and intercellular messengers and as regulatory molecules that play essential roles in signal transduction, inflammation, angiogenesis, and metabolic disorders such as diabetes, neurodegenerative diseases, and cancer cell degeneration. Ceramides also play an important structural role in cell membranes by increasing their rigidity, creating micro-domains (rafts and caveolae), and altering membrane permeability; all these events are involved in the cell signaling. Ceramides constitute approximately half of the lipid composition in the human skin contributing to barrier function as well as epidermal signaling as they affect both proliferation and apoptosis of keratinocytes. Incorporation of ceramides in topical preparations as functional lipids appears to alter skin barrier functions. Ceramides also appear to enhance the bioavailability of drugs by acting as lipid delivery systems. They appear to regulate the ocular inflammation signaling, and external ceramides have shown relief in the anterior and posterior eye disorders. Ceramides play a structural role in liposome formulations and enhance the cellular uptake of amphiphilic drugs, such as chemotherapies. This review presents an overview of the various biological functions of ceramides, and their utility in topical, oral, ocular, and chemotherapeutic drug delivery.
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http://dx.doi.org/10.1208/s12249-019-1497-6DOI Listing
August 2019

Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma.

AAPS PharmSciTech 2019 Jul 11;20(6):250. Epub 2019 Jul 11.

School of Pharmacy and Health Professionals, Creighton University, Omaha, Nebraska, 68178, USA.

Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.
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http://dx.doi.org/10.1208/s12249-019-1457-1DOI Listing
July 2019

Novel 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives produce anticancer efficacy in ovarian cancer .

Heliyon 2019 May 14;5(5):e01603. Epub 2019 May 14.

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

A novel series of 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones were synthesized, using the 'molecular hybridization approach' and evaluated for anticancer efficacy. Eleven 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones ( to ) were synthesized and evaluated for cytotoxic efficacy in cancer (ovarian, prostate and colon) and two non-cancerous cell lines. Among the 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives, with a 6-Cl substitution in the 3-quinolinyl moiety, had selective and potent cytotoxic efficacy in the ovarian cancer cell line A2780. Further mechanistic investigations indicated that significantly inhibited the clonogenic survival of A2780 cancer cells, which was mediated by inducing apoptosis.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522656PMC
May 2019

Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells.

Cancers (Basel) 2019 May 23;11(5). Epub 2019 May 23.

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

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.
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http://dx.doi.org/10.3390/cancers11050711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563099PMC
May 2019

Advances in Ultrasound Mediated Transdermal Drug Delivery.

Curr Pharm Des 2019 ;25(4):413-423

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

Low frequency ultrasound-assisted drug delivery has been widely investigated as a non-invasive method to enhance the transdermal penetration of drugs. Using this technique, a brief application of ultrasound is used to permeabilize skin for a prolonged time. In this review, an overview on ultrasound is detailed to help explain the parameters that could be modulated to obtain the desired ultrasound parameters for enhanced transdermal drug delivery. The mechanisms of enhancement and the latest developments in the area of ultrasound-assisted transdermal drug delivery are discussed. Special emphasis is placed on the effects of ultrasound when used in combination with microneedles, electroporation and iontophoresis, and penetration enhancers. Further, this review summarizes the effect of ultrasound on skin integrity and the regulatory requirements for commercialization of the ultrasound based transdermal delivery instruments.
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http://dx.doi.org/10.2174/1381612825666190211163948DOI Listing
February 2020

Sofosbuvir: A Potential Treatment for Ebola.

Front Pharmacol 2018 10;9:1139. Epub 2018 Oct 10.

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.2018.01139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192451PMC
October 2018

Cariprazine, A Dopamine D₂/D₃ Receptor Partial Agonist, Modulates ABCG2-Mediated Multidrug Resistance in Cancer.

Cancers (Basel) 2018 Sep 4;10(9). Epub 2018 Sep 4.

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

Multidrug resistance (MDR) is a continuing clinical problem that limits the efficacy of chemotherapy in cancer. The over expression of the ATP-binding cassette (ABC) family G2 (ABCG2) transporter is one of the main mechanisms that mediates MDR in cancer. Molecular modeling data indicated that cariprazine, a dopamine D₂/D₃ receptor partial agonist, had a significant binding affinity for ABCG2 transporter with a Glide XP score of -6.515. Therefore, in this in vitro study, we determined the effect of cariprazine on MDR resulting from the overexpression of ABCG2 transporters. Alone, cariprazine, at concentrations up to 20 μM, did not significantly decrease cell viability. Cariprazine, at concentrations ranging from 1 to 10 μM, did not significantly alter the cytotoxicity of mitoxantrone (MX) in the parental non-small cell cancer cell line, H460 and colon cancer cell S1. However, cariprazine (1⁻20 μM) significantly enhanced the efficacy of ABCG2 substrate antineoplastic drug MX in the ABCG2-overexpressing MDR cell line, H460-MX20 and S1M1-80, by reducing the resistance fold from 28 to 1 and from 93 to 1.33, respectively. Cariprazine, in a concentration-dependent (1⁻20 μM), significantly increased the intracellular accumulation of Rhodamine 123 in S1M1-80. Interestingly, 10 or 20 μM of cariprazine significantly decreased the expression levels of the ABCG2 protein in the colon and lung cancer cell lines, suggesting that cariprazine inhibits both the function and expression of ABCG2 transporters at nontoxic concentrations. Overall, our results suggest that cariprazine, via several distinct mechanisms, can resensitize resistant cancer cells to mitoxantrone.
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http://dx.doi.org/10.3390/cancers10090308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162716PMC
September 2018

Alcohol and Cocaine Exposure Modulates ABCB1 and ABCG2 Transporters in Male Alcohol-Preferring Rats.

Mol Neurobiol 2019 Mar 6;56(3):1921-1932. Epub 2018 Jul 6.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA.

Two efflux transporters, ATP-binding cassettes B1 (ABCB1) and G2 (ABCG2), are highly expressed in the endothelial cells of the brain, where they regulate the bioavailability and distribution of several endogenous and xenobiotic compounds. However, whether ABCB1 or ABCG2 has any link with drug dependence, drug withdrawal effects, or the incidence of adverse effects in drug abuser is not known. In this study, we determined the effects of voluntary ethanol consumption following repeated exposure to cocaine or vehicle on the relative mRNA and protein expression of Abcg2/ABCG2 and Abcb1/ABCB1 in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of male alcohol-preferring (P) rats. Male P rats were allowed free choice access to ethanol (15 and 30% v/v) and water for 5 weeks to establish baseline drinking behavior. The following week, rats were either injected with 20 mg/kg i.p. of cocaine or saline, once a day, for 7 days. The relative mRNA and protein expression of Abcb1/ABCB1 and Abcg2/ABCG2 in the NAc and mPFC were significantly decreased in ethanol-saline- and ethanol-cocaine-exposed rats compared to control rats that received neither ethanol nor cocaine. Thus, prolonged exposure to commonly abused drugs, ethanol and cocaine, alters the expression of Abcb1/ABCB1 and Abcg2/ABCG2 mRNA and protein levels in brain areas that play a role in drug dependence.
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http://dx.doi.org/10.1007/s12035-018-1153-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780301PMC
March 2019

Modulation of the ATP-Binding Cassette B1 Transporter by Neuro-Inflammatory Cytokines: Role in the Pathogenesis of Alzheimer's Disease.

Front Pharmacol 2018 20;9:658. Epub 2018 Jun 20.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.3389/fphar.2018.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020013PMC
June 2018

Bax/Tubulin/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis.

Front Pharmacol 2018 23;9:520. Epub 2018 May 23.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States.

The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a-15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, , 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in a CRC animal model for further development.
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http://dx.doi.org/10.3389/fphar.2018.00520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974752PMC
May 2018

lH-Pyrazolo[3,4-b]quinolin-3-amine derivatives inhibit growth of colon cancer cells via apoptosis and sub G1 cell cycle arrest.

Bioorg Med Chem Lett 2018 07 24;28(13):2244-2249. Epub 2018 May 24.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, OH, USA; Department of Biomedical Sciences, Tuskegee University, Tuskegee, AL, USA. Electronic address:

A series of lH-pyrazolo[3,4-b]quinolin-3-amine derivatives were synthesized and evaluated for anticancer efficacy in a panel of ten cancer cell lines, including breast (MDAMB-231 and MCF-7), colon (HCT-116, HCT-15, HT-29 and LOVO), prostate (DU-145 and PC3), brain (LN-229), ovarian (A2780), and human embryonic kidney (HEK293) cells, a non-cancerous cell line. Among the eight derivatives screened, compound QTZ05 had the most potent and selective antitumor efficacy in the four colon cancer cell lines, with IC values ranging from 2.3 to 10.2 µM. Furthermore, QTZ05 inhibited colony formation in HCT-116 cells in a concentration-dependent manner. Cell cycle analysis data indicated that QTZ05 caused an arrest in the sub G1 cell cycle in HCT-116 cells. QTZ05 induced apoptosis in HCT-116 cells in a concentration-dependent manner that was characterized by chromatin condensation and increase in the fluorescence of fluorochrome-conjugated Annexin V. The findings from our study suggest that QTZ05 may be a valuable prototype for the development of chemotherapeutics targeting apoptotic pathways in colorectal cancer cells.
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http://dx.doi.org/10.1016/j.bmcl.2018.05.045DOI Listing
July 2018