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Bone Marrow-Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism.
Bloodworth NC, Clark CR, West JD, Snider JC, Gaskill C, Shay S, Scott C, Bastarache J, Gladson S, Moore C, D'Amico R, Brittain EL, Tanjore H, Blackwell TS, Majka SM, Merryman WD
(2018) Circ Res 123: e51-e64
MeSH Terms: Angiogenesis Inhibitors, Animals, Arterioles, Cell Lineage, Cells, Cultured, Hypertension, Pulmonary, Indoles, Lung, Mice, Mice, Inbred C57BL, Myeloid Progenitor Cells, Pyrroles, Receptor, Serotonin, 5-HT2B, Vascular Stiffness
Show Abstract · Added April 2, 2019
RATIONALE - Pulmonary arterial hypertension is a deadly disease of the pulmonary vasculature for which no disease-modifying therapies exist. Small-vessel stiffening and remodeling are fundamental pathological features of pulmonary arterial hypertension that occur early and drive further endovascular cell dysfunction. Bone marrow (BM)-derived proangiogenic cells (PACs), a specialized heterogeneous subpopulation of myeloid lineage cells, are thought to play an important role in pathogenesis.
OBJECTIVE - To determine whether BM-derived PACs directly contributed to experimental pulmonary hypertension (PH) by promoting small-vessel stiffening through 5-HT (serotonin 2B receptor)-mediated signaling.
METHODS AND RESULTS - We performed BM transplants using transgenic donor animals expressing diphtheria toxin secondary to activation of an endothelial-specific tamoxifen-inducible Cre and induced experimental PH using hypoxia with SU5416 to enhance endovascular injury and ablated BM-derived PACs, after which we measured right ventricular systolic pressures in a closed-chest procedure. BM-derived PAC lineage tracing was accomplished by transplanting BM from transgenic donor animals with fluorescently labeled hematopoietic cells and treating mice with a 5-HT antagonist. BM-derived PAC ablation both prevented and reversed experimental PH with SU5416-enhanced endovascular injury, reducing the number of muscularized pulmonary arterioles and normalizing arteriole stiffness as measured by atomic force microscopy. Similarly, treatment with a pharmacological antagonist of 5-HT also prevented experimental PH, reducing the number and stiffness of muscularized pulmonary arterioles. PACs accelerated pulmonary microvascular endothelial cell injury response in vitro, and the presence of BM-derived PACs significantly correlated with stiffer pulmonary arterioles in pulmonary arterial hypertension patients and mice with experimental PH. RNA sequencing of BM-derived PACs showed that 5-HT antagonism significantly altered biologic pathways regulating cell proliferation, locomotion and migration, and cytokine production and response to cytokine stimulus.
CONCLUSIONS - Together, our findings illustrate that BM-derived PACs directly contribute to experimental PH with SU5416-enhanced endovascular injury by mediating small-vessel stiffening and remodeling in a 5-HT signaling-dependent manner.
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14 MeSH Terms
Light-activatable cannabinoid prodrug for combined and target-specific photodynamic and cannabinoid therapy.
Ling X, Zhang S, Liu Y, Bai M
(2018) J Biomed Opt 23: 1-9
MeSH Terms: Animals, Antineoplastic Agents, Cannabinoids, Cell Line, Tumor, Cell Survival, HEK293 Cells, Humans, Indoles, Mice, Organosilicon Compounds, Photochemotherapy, Photosensitizing Agents, Prodrugs, Reactive Oxygen Species
Show Abstract · Added April 2, 2019
Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.
(2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).
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14 MeSH Terms
Combined CB2 receptor agonist and photodynamic therapy synergistically inhibit tumor growth in triple negative breast cancer.
Zhang J, Zhang S, Liu Y, Su M, Ling X, Liu F, Ge Y, Bai M
(2018) Photodiagnosis Photodyn Ther 24: 185-191
MeSH Terms: Acetamides, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Combined Modality Therapy, Female, Gene Expression Regulation, Neoplastic, Humans, Indoles, Mice, Neoplasm Recurrence, Local, Phenyl Ethers, Photochemotherapy, Photosensitizing Agents, Quality of Life, Receptor, Cannabinoid, CB2, Receptors, GABA, Singlet Oxygen, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CBR, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CBR agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CBR agonists for cancer.
Copyright © 2018 Elsevier B.V. All rights reserved.
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22 MeSH Terms
Mechanistic insight into the interaction of gastrointestinal mucus with oral diblock copolymers synthesized via ATRP method.
Liu J, Cao J, Cao J, Han S, Liang Y, Bai M, Sun Y
(2018) Int J Nanomedicine 13: 2839-2856
MeSH Terms: Administration, Oral, Animals, Caco-2 Cells, Drug Carriers, Humans, Hydrophobic and Hydrophilic Interactions, Indoles, Intestinal Absorption, Intestinal Mucosa, Male, Methacrylates, Methylmethacrylates, Mice, Nanoparticles, Nylons, Particle Size, Polymers, Propionates, Tissue Distribution
Show Abstract · Added April 2, 2019
Introduction - Nanoparticles are increasingly used as drug carriers for oral administration. The delivery of drug molecules is largely dependent on the interaction of nanocarriers and gastrointestinal (GI) mucus, a critical barrier that regulates drug absorption. It is therefore important to understand the effects of physical and chemical properties of nanocarriers on the interaction with GI mucus. Unfortunately, most of the nanoparticles are unable to be prepared with satisfactory structural monodispersity to comprehensively investigate the interaction. With controlled size, shape, and surface chemistry, copolymers are ideal candidates for such purpose.
Materials and methods - We synthesized a series of diblock copolymers via the atom transfer radical polymerization method and investigated the GI mucus permeability in vitro and in vivo.
Results - Our results indicated that uncharged and hydrophobic copolymers exhibited enhanced GI absorption.
Conclusion - These results provide insights into developing optimal nanocarriers for oral administration.
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Advocating for mutually beneficial access to shelved compounds.
Pulley JM, Jerome RN, Shirey-Rice JK, Zaleski NM, Naylor HM, Pruijssers AJ, Jackson JC, Bernard GR, Holroyd KJ
(2018) Future Med Chem 10: 1395-1398
MeSH Terms: Antidiuretic Hormone Receptor Antagonists, Anxiety Disorders, Depressive Disorder, Major, Drug Industry, Drug Repositioning, Humans, Indoles, Pyrrolidines, Receptors, Vasopressin
Added March 26, 2019
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PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems.
Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ
(2018) ACS Chem Neurosci 9: 2218-2224
MeSH Terms: Allosteric Regulation, Animals, CHO Cells, Calcium, Cricetulus, Dogs, Humans, Isoindoles, Mice, Oxazoles, Patch-Clamp Techniques, Prefrontal Cortex, Rats, Receptor, Muscarinic M1, Seizures
Show Abstract · Added March 3, 2020
Positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M PAMs may reduce efficacy and contribute to adverse effect liability. However, the M PAM PF-06827443 was reported to have only weak agonist activity at human M receptors but produced M-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.
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The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer.
Wilson AJ, Stubbs M, Liu P, Ruggeri B, Khabele D
(2018) Gynecol Oncol 149: 575-584
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, BRCA1 Protein, Carcinoma, Ovarian Epithelial, Cell Cycle Proteins, Cell Line, Tumor, Down-Regulation, Drug Synergism, Female, Homologous Recombination, Humans, Indoles, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasms, Glandular and Epithelial, Nuclear Proteins, Organic Chemicals, Ovarian Neoplasms, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Transcription Factors, Xenograft Model Antitumor Assays
Show Abstract · Added March 3, 2020
OBJECTIVE - Homologous recombination (HR)-proficient ovarian tumors have poorer clinical outcomes and show resistance to poly ADP ribose polymerase inhibitors (PARPi). A subset of HR-proficient ovarian tumors show amplification in bromodomain and extra-terminal (BET) genes such as BRD4. We aimed to test the hypothesis that BRD4 inhibition sensitizes ovarian cancer cells to PARPi by reducing HR efficiency and increasing DNA damage.
METHODS - HR-proficient ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3, UWB1.289+BRCA1) were treated with BRD4-targeting siRNA, novel (INB054329, INCB057643) and established (JQ1) BET inhibitors (BETi) and PARPi (olaparib, rucaparib). Cell growth and viability were assessed by sulforhodamine B assays in vitro, and in SKOV-3 and ovarian cancer patient-derived xenografts in vivo. DNA damage and repair (pH2AX, RAD51 and BRCA1 foci formation, and DRGFP HR reporter activity), apoptosis markers (cleaved PARP, cleaved caspase-3, Bax) and proliferation markers (PCNA, Ki67) were assessed by immunofluorescence and western blot.
RESULTS - In cultured cells, inhibition of BRD4 by siRNA or INCB054329 reduced expression and function of BRCA1 and RAD51, reduced HR reporter activity, and sensitized the cells to olaparib-induced growth inhibition, DNA damage induction and apoptosis. Synergy was observed between all BETi tested and PARPi. INCB054329 and olaparib also co-operatively inhibited xenograft tumor growth, accompanied by reduced BRCA1 expression and proliferation, and increased apoptosis and DNA damage.
CONCLUSIONS - These results provide strong rationale for using BETi to extend therapeutic efficacy of PARPi to HR-proficient ovarian tumors and could benefit a substantial number of women diagnosed with this devastating disease.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Muscarinic M receptors modulate ethanol seeking in rats.
Berizzi AE, Perry CJ, Shackleford DM, Lindsley CW, Jones CK, Chen NA, Sexton PM, Christopoulos A, Langmead CJ, Lawrence AJ
(2018) Neuropsychopharmacology 43: 1510-1517
MeSH Terms: Animals, Conditioning, Operant, Corpus Striatum, Cues, Drug-Seeking Behavior, Ethanol, Imidazoles, Indoles, Locomotion, Male, Microinjections, Rats, Receptor, Muscarinic M5, Self Administration, Sucrose, Varenicline
Show Abstract · Added March 18, 2020
Despite the cost to both individual and society, alcohol use disorders (AUDs) remain a major health risk within society, and both relapse and heavy drinking are still poorly controlled with current medications. Here we demonstrate for the first time that a centrally active and selective negative allosteric modulator for the rat M muscarinic acetylcholine receptor (mAChR), ML375, decreases ethanol self-administration and attenuates cue-induced reinstatement of ethanol seeking in ethanol-preferring (iP) rats. Importantly, ML375 did not affect sucrose self-administration or general locomotor activity indicative of a selective effect on ethanol seeking. Based on the expression profile of M mAChRs in the brain and the distinct roles different aspects of the dorsal striatum have on long-term and short-term ethanol use, we studied whether intra-striatal microinjection of ML375 modulated ethanol intake in rats. We show in iP rats with an extensive history of ethanol intake that intra-dorsolateral (DL), but not intra-dorsomedial, striatal injections of ML375 reduced ethanol self-administration to a similar extent as the nicotinic acetylcholine receptor ligand varenicline, which has preclinical and clinical efficacy in reducing the reinforcing effects of ethanol. These data implicate the DL striatum as a locus for the effects of cholinergic-acting drugs on ethanol seeking in rats with a history of long-term ethanol use. Accordingly, we demonstrate in rats that selectively targeting the M mAChR can modulate both voluntary ethanol intake and cue-induced ethanol seeking and thereby provide direct evidence that the M mAChR is a potential novel target for pharmacotherapies aimed at treating AUDs.
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Toxicity and repair of DNA adducts produced by the natural product yatakemycin.
Mullins EA, Shi R, Eichman BF
(2017) Nat Chem Biol 13: 1002-1008
MeSH Terms: Biological Products, DNA Adducts, DNA Damage, DNA Repair, Drug Resistance, Bacterial, Duocarmycins, Indoles, Molecular Structure, Pyrroles
Show Abstract · Added August 26, 2019
Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.
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9 MeSH Terms
Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.
Hardeman KN, Peng C, Paudel BB, Meyer CT, Luong T, Tyson DR, Young JD, Quaranta V, Fessel JP
(2017) Sci Rep 7: 42604
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Drug Resistance, Neoplasm, Glucose, Glycolysis, Humans, Indoles, Melanoma, Molecular Targeted Therapy, Mutation, Oncogenes, Pharmacogenomic Variants, Phenotype, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides, Treatment Outcome
Show Abstract · Added April 18, 2017
Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.
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17 MeSH Terms