Myxoma Virus Expressing Interleukin-15 Fails To Cause Lethal Myxomatosis in European Rabbits

ABSTRACT Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy.

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A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22168372 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8372

Author(s):

Ana María Zárate ◽

Christian Espinosa-Bustos ◽

Simón Guerrero ◽

Angélica Fierro ◽

Felipe Oyarzún-Ampuero ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Antitumour Activity ◽

Anticancer Compounds ◽

Human Cancer Cells ◽

Cycle Arrest ◽

Apoptosis Inducer ◽

Purine Ring

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

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Overexpressed Pituitary Tumor-Transforming Gene Causes Aneuploidy in Live Human Cells

Endocrinology ◽

10.1210/en.2003-0305 ◽

2003 ◽

Vol 144 (11) ◽

pp. 4991-4998 ◽

Cited By ~ 76

Author(s):

Run Yu ◽

Wenge Lu ◽

Jiandong Chen ◽

Chris J. McCabe ◽

Shlomo Melmed

Keyword(s):

Cancer Cells ◽

Chromosome Segregation ◽

Pituitary Tumor ◽

Fluorescent Protein ◽

Human Cancer ◽

Live Cells ◽

Pituitary Tumor Transforming Gene ◽

Transforming Gene

Abstract The mammalian securin, pituitary tumor-transforming gene (PTTG), is overexpressed in several tumors and transforms cells in vitro and in vivo. To test the hypothesis that PTTG overexpression causes aneuploidy, enhanced green fluorescent protein (EGFP)-tagged PTTG (PTTG-EGFP) was expressed in human H1299 cancer cells (with undetectable endogenous PTTG expression) and mitosis of individual live cells observed. Untransfected cells and cells expressing EGFP alone exhibited appropriate mitosis. PTTG-EGFP markedly prolonged prophase and metaphase, indicating that PTTG blocks progression of mitosis to anaphase. In cells that underwent apparently normal mitosis (35 of 65 cells), PTTG-EGFP was degraded about 1 min before anaphase onset. Cells that failed to degrade PTTG-EGFP exhibited asymmetrical cytokinesis without chromosome segregation (18 of 65 cells) or chromosome decondensation without cytokinesis (9 of 65 cells), resulting in appearance of a macronucleus. Fifty-one of 55 cells expressing a nondegradable mutant PTTG exhibited asymmetrical cytokinesis without chromosome segregation, and some (4 of 55) decondensed chromosomes, both resulting in macronuclear formation. During this abnormal cytokinesis, all chromosomes and spindles and both centrosomes moved to one daughter cell, suggesting potential chaos in the subsequent mitosis. In conclusion, failure of PTTG degradation or enhanced PTTG accumulation, as a consequence of overexpression, inhibits mitosis progression and chromosome segregation but does not directly affect cytokinesis, resulting in aneuploidy. These results demonstrate that PTTG induces aneuploidy in single, live, human cancer cells.

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Cardiovascular, carcinogenic and reproductive effects of nicotine exposure: A narrative review of the scientific literature

F1000Research ◽

10.12688/f1000research.20062.2 ◽

2020 ◽

Vol 8 ◽

pp. 1586

Author(s):

Leonie R. Price ◽

Javier Martinez

Keyword(s):

Cardiovascular Risk ◽

Cancer Progression ◽

Animal Studies ◽

Scientific Literature ◽

Human Cancer ◽

Narrative Review ◽

Nicotine Exposure ◽

Health Related

The emergence of new tobacco heating products and electronic nicotine delivery systems (ENDS) is changing the way humans are exposed to nicotine. The purpose of this narrative review is to provide a broad overview of published scientific literature with respect to the effects of nicotine on three key health-related areas: 1) cardiovascular risk, 2) carcinogenesis and 3) reproductive outcomes. These areas are known to be particularly vulnerable to the effects of cigarette smoke, and in addition, nicotine has been hypothesized to play a role in disease pathogenesis. Acute toxicity will also be discussed. The literature to February 2019 suggests that there is no increased cardiovascular risk of nicotine exposure in consumers who have no underlying cardiovascular pathology. There is scientific consensus that nicotine is not a direct or complete carcinogen, however, it remains to be established whether it plays some role in human cancer propagation and metastasis. These cancer progression pathways have been proposed in models in vitro and in transgenic rodent lines in vivo but have not been demonstrated in cases of human cancer. Further studies are needed to determine whether nicotine is linked to decreased fertility in humans. The results from animal studies indicate that nicotine has the potential to act across many mechanisms during fetal development. More studies are needed to address questions regarding nicotine exposure in humans, and this may lead to additional guidance concerning new ENDS entering the market.

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Induction of apoptosis by in vitro and in vivo plant extracts derived from Menyanthes trifoliata L. in human cancer cells

Cytotechnology ◽

10.1007/s10616-018-0274-9 ◽

2019 ◽

Vol 71 (1) ◽

pp. 165-180 ◽

Cited By ~ 11

Author(s):

Tomasz Kowalczyk ◽

Przemysław Sitarek ◽

Ewa Skała ◽

Monika Toma ◽

Marzena Wielanek ◽

...

Keyword(s):

Cancer Cells ◽

Plant Extracts ◽

Human Cancer ◽

Human Cancer Cells ◽

Induction Of Apoptosis ◽

Menyanthes Trifoliata

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Positive interactions between human interferon and cepharanthin against human cancer cells in vitro and in vivo

Cancer Chemotherapy and Pharmacology ◽

10.1007/bf00686278 ◽

1994 ◽

Vol 35 (1) ◽

pp. 10-16 ◽

Cited By ~ 8

Author(s):

Minoru Ono ◽

Noriaki Tanaka ◽

Kunzo Orita

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Human Interferon ◽

Positive Interactions ◽

Human Cancer Cells

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Protein kinase D inhibits plasma membrane Na+/H+exchanger activity

AJP Cell Physiology ◽

10.1152/ajpcell.1999.277.6.c1202 ◽

1999 ◽

Vol 277 (6) ◽

pp. C1202-C1209 ◽

Cited By ~ 33

Author(s):

Robert S. Haworth ◽

James Sinnett-Smith ◽

Enrique Rozengurt ◽

Metin Avkiran

Keyword(s):

Plasma Membrane ◽

Protein Kinase ◽

Phorbol Ester ◽

Fluorescent Protein ◽

Dominant Negative ◽

Protein Kinase D ◽

Wild Type ◽

Ph Indicator

The regulation of plasma membrane Na+/H+exchanger (NHE) activity by protein kinase D (PKD), a novel protein kinase C- and phorbol ester-regulated kinase, was investigated. To determine the effect of PKD on NHE activity in vivo, intracellular pH (pHi) measurements were made in COS-7 cells by microepifluorescence using the pH indicator cSNARF-1. Cells were transfected with empty vector (control), wild-type PKD, or its kinase-deficient mutant PKD-K618M, together with green fluorescent protein (GFP). NHE activity, as reflected by the rate of acid efflux ( J H), was determined in single GFP-positive cells following intracellular acidification. Overexpression of wild-type PKD had no significant effect on J H(3.48 ± 0.25 vs. 3.78 ± 0.24 mM/min in control at pHi 7.0). In contrast, overexpression of PKD-K618M increased J H (5.31 ± 0.57 mM/min at pHi 7.0; P < 0.05 vs. control). Transfection with these constructs produced similar effects also in A-10 cells, indicating that native PKD may have an inhibitory effect on NHE in both cell types, which is relieved by a dominant-negative action of PKD-K618M. Exposure of COS-7 cells to phorbol ester significantly increased J H in control cells but failed to do so in cells overexpressing either wild-type PKD (due to inhibition by the overexpressed PKD) or PKD-K618M (because basal J Hwas already near maximal). A fusion protein containing the cytosolic regulatory domain (amino acids 637–815) of NHE1 (the ubiquitous NHE isoform) was phosphorylated in vitro by wild-type PKD, but with low stoichiometry. These data suggest that PKD inhibits NHE activity, probably through an indirect mechanism, and represents a novel pathway in the regulation of the exchanger.

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Actions and Potential Therapeutic Applications of Growth Hormone–Releasing Hormone Agonists

Endocrinology ◽

10.1210/en.2019-00111 ◽

2019 ◽

Vol 160 (7) ◽

pp. 1600-1612 ◽

Cited By ~ 11

Author(s):

Andrew V Schally ◽

Xianyang Zhang ◽

Renzhi Cai ◽

Joshua M Hare ◽

Riccarda Granata ◽

...

Keyword(s):

Cell Proliferation ◽

Cardiac Tissue ◽

Human Cancer ◽

Large Body ◽

Neuroprotective Effects ◽

Promote Cell Proliferation ◽

Therapeutic Applications ◽

Human Cancer Cells

Abstract In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use.

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