Combined therapy with COX-2 inhibitor and 20-HETE inhibitor reduces colon tumor growth and the adverse effects of ischemic stroke associated with COX-2 inhibition

20-Hydroxyeicosatetraenoic acid (20-HETE), Cyp4a-derived eicosanoid, is a lipid mediator that promotes tumor growth, as well as causing detrimental effects in cerebral circulation. We determined whether concurrent inhibition of cyclooxygenase-2 (COX-2) and 20-HETE affects colon tumor growth and ischemic stroke outcomes. The expression of Cyp4a and COXs and production of 20-HETE and PGE2 were determined in murine colon carcinoma (MC38) cells. We then examined the effects of combined treatment with rofecoxib, a potent COX-2 inhibitor, and HET0016, a potent Cyp4a inhibitor, on the growth and proliferation of MC38 cells. Subsequently, we tested the effects of HET0016 plus rofecoxib in MC38 tumor and ischemic stroke models. Cyp4a and COXs are highly expressed in MC38 cells. Respectively, HET0016 and rofecoxib inhibited 20-HETE and PGE2 formation in MC38 cells. Moreover, rofecoxib combined with HET0016 had greater inhibitory effects on the growth and proliferation of MC38 cells than did rofecoxib alone. Importantly, rofecoxib combined with HET0016 provided greater inhibition on tumor growth than did rofecoxib alone in MC38 tumor-bearing mice. Prolonged treatment with rofecoxib selectively induced circulating 20-HETE levels and caused cerebrovascular damage after ischemic stroke, whereas therapy with rofecoxib and HET0016 attenuated 20-HETE levels and reduced rofecoxib-induced cerebrovascular damage and stroke outcomes during anti-tumor therapy. Thus these results demonstrate that combination therapy with rofecoxib and HET0016 provides a new treatment of colon tumor, which can not only enhance the anti-tumor efficacy of rofecoxib, but also reduce rofecoxib-induced cerebrovascular damage and stroke outcomes.

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Combined Therapy With Avastin, a PAF Receptor Antagonist and a Lipid Mediator Inhibited Glioblastoma Tumor Growth

Frontiers in Pharmacology ◽

10.3389/fphar.2021.746470 ◽

2021 ◽

Vol 12 ◽

Author(s):

Valerie A. Cruz Flores ◽

Hemant Menghani ◽

Pranab K. Mukherjee ◽

Luis Marrero ◽

Andre Obenaus ◽

...

Keyword(s):

Synergistic Effect ◽

Tumor Growth ◽

Receptor Antagonist ◽

Ex Vivo ◽

Combined Therapy ◽

Lipid Mediator ◽

Cell Integrity ◽

Current Standard ◽

Saline Treatment ◽

Post Implantation

Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.

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Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1803999116 ◽

2019 ◽

Vol 116 (5) ◽

pp. 1698-1703 ◽

Cited By ~ 28

Author(s):

Allison Gartung ◽

Jun Yang ◽

Vikas P. Sukhatme ◽

Diane R. Bielenberg ◽

Djanira Fernandes ◽

...

Keyword(s):

Tumor Growth ◽

Tumor Progression ◽

Ovarian Tumor ◽

Lipid Mediators ◽

Lipid Mediator ◽

Bioactive Lipids ◽

First Line ◽

Proinflammatory Mediators ◽

Dual Inhibition ◽

Cox 2

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived “surge” of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.

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Nanoparticle-encapsulated doxorubicin enhances cryoablation of cancer stem-like cells

TECHNOLOGY ◽

10.1142/s2339547814500022 ◽

2014 ◽

Vol 02 (01) ◽

pp. 28-35 ◽

Cited By ~ 12

Author(s):

Wei Rao ◽

Adriano Bellotti ◽

Peter J. Littrup ◽

Jianhua Yu ◽

Xiongbin Lu ◽

...

Keyword(s):

Minimally Invasive ◽

Tumor Growth ◽

Cancer Treatment ◽

Combined Therapy ◽

Combined Treatment ◽

Complete Elimination ◽

Conventional Chemotherapy ◽

Free Doxorubicin ◽

The Individual

Cryoablation is a promising minimally invasive technology for cancer treatment. However, no study was reported concerning the effect of cryoablation on cancer stem-like cells (CSCs) that are capable of reinitiating tumor growth after conventional chemotherapy. Using a biomimetic 3D mammosphere model, we found that cryoablation alone could significantly but incompletely destroy CD44+CD133+ CSCs. Moreover, the combination of cryoablation and conventional chemotherapy using free doxorubicin (fDOX) does not significantly enhance destruction of the CSCs over the individual treatments. We develop a novel combined treatment of cryoablation and nanoparticle-encapsulated doxorubicin (nDOX) that is capable of achieving nearly complete elimination of the CSCs (from 16.6 to 0.6%). This is attributed in part to the much-enhanced uptake of nDOX (compared to fDOX) by the CSCs. Collectively, this study demonstrates the great potential of a combined therapy of cryoablation and nanodrug for improved cancer treatment by eliminating the root of cancer — the CSCs.

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COMBINATION OF POTASSIUM PERCHLORATE AND PROPYLTHIOURACIL IN THE TREATMENT OF THYROTOXICOSIS

Acta Endocrinologica ◽

10.1530/acta.0.0570565 ◽

1968 ◽

Vol 57 (4) ◽

pp. 565-577 ◽

Cited By ~ 4

Author(s):

K. E. Røkke ◽

J. H. Vogt

Keyword(s):

Drug Therapy ◽

Side Effects ◽

Metabolic Rate ◽

Total Cholesterol ◽

Basal Metabolic Rate ◽

Combined Therapy ◽

Combined Treatment ◽

Control Measures ◽

Potassium Perchlorate ◽

Plasma Total Cholesterol

ABSTRACT A report is given on 95 thyrotoxic patients treated with a combination of 400 mg propylthiouracil and 400 mg of potassium perchlorate. Perchlorate was stopped when a marked remission of symptoms was obtained, on an average after less than 7 weeks. Euthyroidism was found on an average after 7.2 weeks. The basal metabolic rate, PBI, plasma total cholesterol and weight showed a fairly rapid normalization. Thirteen of the 95 patients were given radio-iodine therapy shortly before drug therapy was started. The remaining 82 cases were grouped together with the 23 cases previously reported. Of the total of 105 cases, 96 became euthyroid on combined therapy. For the frequency of side-effects, the thirteen cases mentioned above were included, giving a total of 118 cases. Eight cases showed an increase in goitre size and 15 cases had other side-effects, of which three were granulocytopenia due to propylthiouracil. The possibility of a higher frequency of mainly minor side-effects on combined therapy has to be balanced against the seemingly rapid and reliable therapeutic effect. Combined treatment, perhaps with even smaller doses than reported here, can be recommended in selected cases of thyrotoxicosis where a shortening of the thyrotoxic state seems of importance, or possibly where difficulties due to iodine exposure may be anticipated, provided adequate control measures are taken.

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Persistent luminescence nanoparticles for cancer theranostics application

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00862-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Nian Liu ◽

Xiao Chen ◽

Xia Sun ◽

Xiaolian Sun ◽

Junpeng Shi

Keyword(s):

Uv Light ◽

Combined Therapy ◽

Tumor Therapy ◽

High Sensitivity ◽

Persistent Luminescence ◽

Therapeutic Drugs ◽

High Penetration ◽

Recent Developments ◽

Cancer Theranostics

AbstractPersistent luminescence nanoparticles (PLNPs) are unique optical materials that emit afterglow luminescence after ceasing excitation. They exhibit unexpected advantages for in vivo optical imaging of tumors, such as autofluorescence-free, high sensitivity, high penetration depth, and multiple excitation sources (UV light, LED, NIR laser, X-ray, and radiopharmaceuticals). Besides, by incorporating other functional molecules, such as photosensitizers, photothermal agents, or therapeutic drugs, PLNPs are also widely used in persistent luminescence (PersL) imaging-guided tumor therapy. In this review, we first summarize the recent developments in the synthesis and surface functionalization of PLNPs, as well as their toxicity studies. We then discuss the in vivo PersL imaging and multimodal imaging from different excitation sources. Furthermore, we highlight PLNPs-based cancer theranostics applications, such as fluorescence-guided surgery, photothermal therapy, photodynamic therapy, drug/gene delivery and combined therapy. Finally, future prospects and challenges of PLNPs in the research of translational medicine are also discussed.

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A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

Scientific Reports ◽

10.1038/s41598-021-94837-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

A. Farias ◽

A. Soto ◽

F. Puttur ◽

C. J. Goldin ◽

S. Sosa ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Therapeutic Effect ◽

Immune Cells ◽

Immune Checkpoint ◽

Combined Treatment ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Regulatory Cells ◽

Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

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Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells

BMC Cancer ◽

10.1186/s12885-021-08188-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Helena de Castro e Gloria ◽

Laura Jesuíno Nogueira ◽

Patrícia Bencke Grudzinski ◽

Paola Victória da Costa Ghignatti ◽

Temenouga Nikolova Guecheva ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Mismatch Repair ◽

Cell Cycle Progression ◽

Combined Therapy ◽

Combined Treatment ◽

Human Colon ◽

Human Colon Cancer

Abstract Background The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. Methods Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. Results Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. Conclusion Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

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Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Journal of Neuroinflammation ◽

10.1186/s12974-021-02170-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Dong-Ling Liu ◽

Zhi Hong ◽

Jing-Ying Li ◽

Yu-Xin Yang ◽

Chu Chen ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Middle Cerebral Artery ◽

Combined Treatment ◽

Scavenger Receptor ◽

Hemorrhagic Transformation ◽

Microglial Cells ◽

Peroxiredoxin 1 ◽

Macrophage Scavenger Receptor ◽

Tissue Plasminogen

Abstract Background Hemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells. Methods The tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1−/−) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1−/− mice. Results Seventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1−/− mice, respectively. Conclusion The phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

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Combined Peritoneal Dialysis and Hemodialysis: Our Experience Compared to Others

Peritoneal Dialysis International ◽

10.1177/089686080302300211 ◽

2003 ◽

Vol 23 (2) ◽

pp. 157-161 ◽

Cited By ~ 18

Author(s):

Mamta Agarwal ◽

Patricia Clinard ◽

John M. Burkart

Keyword(s):

Peritoneal Dialysis ◽

Control Volume ◽

Combined Therapy ◽

Care Center ◽

Combined Treatment ◽

Tertiary Care ◽

Clinical Reason ◽

Combined Modality ◽

Number Of Patients ◽

Solute Clearance

Objective To determine the clinical experience of using combined-modality [simultaneous hemodialysis (HD) and peritoneal dialysis (PD)] treatment in patients with end-stage renal disease. Design We reviewed data on 4 patients from our center that were treated with “combined-mode therapy.” We then conducted a retrospective survey by sending questionnaires to nephrologists in the US and Canada by mail and by posting the survey on the Internet. Data queried included number of patients on combined modality, solute clearances, albumin levels pre and post combined therapy, reasons for using combined therapy, duration and success of combined therapy, and reimbursement issues. Setting and Participants Ours is a tertiary-care center. Patients that were not doing well on PD alone were put on combined modality of treatment between 1992 and 1998. Main Outcome Measures Clinical improvement in the indication for which the participant was started on combined modality. Results In response to the survey, data on 27 patients were collected. These data were combined with data on 4 patients from our unit that had previously been treated with combined HD and PD. Most patients were reported to have more than one clinical reason for changing from PD to combined therapy. The main clinical reason for offering combined treatments was inadequate solute clearance (34%), followed by ultrafiltration problems (16%) and neuropathy (11%). Mean duration of time followed on combined treatment was 8.5 ± 0.12 months. Most patients tolerated combined treatment well and were reported to show improvement in the clinical reasons for which they needed the combined modality. Dual access and reimbursement issues were not a problem. There was no single method used for calculating total (HD, PD, and residual renal) solute clearance. No universal total solute clearance goal was reported. Conclusion Hemodialysis and PD are not mutually exclusive. They can be used in combination to achieve targeted solute clearances, to improve certain clinical conditions, and to control volume and blood pressure in a subset of patients. Further evaluation is needed to better establish the long-term outcomes of using combined modality. Total solute clearance goals and methods for determining total solute clearance need to be standardized.

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