The Synergistic Effect of Combined Treatment with Systemic Ketamine and Morphine on Experimentally Induced Windup-Like Pain in Humans

OBJECTIVES/GOALS: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. METHODS/STUDY POPULATION: Sixty-four participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy–Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants’ whole blood. An ADT/RT-induced fatigue mouse model was developed with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using Western blot analysis of Glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). RESULTS/ANTICIPATED RESULTS: Fatigue in the ADT group was exacerbated during RT compared to the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated a synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model, and its mechanism may be related to bioenergetics in the CNS.

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Synergistic effect of combined treatment with gamma-tocotrienol and statin on human malignant mesothelioma cells

Cancer Letters ◽

10.1016/j.canlet.2013.07.015 ◽

2013 ◽

Vol 339 (1) ◽

pp. 116-127 ◽

Cited By ~ 12

Author(s):

Guligena Tuerdi ◽

Saki Ichinomiya ◽

Hiromi Sato ◽

Sana Siddig ◽

Eriko Suwa ◽

...

Keyword(s):

Synergistic Effect ◽

Malignant Mesothelioma ◽

Combined Treatment ◽

Gamma Tocotrienol

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Isobolographic Analysis Demonstrates the Additive and Synergistic Effects of Gemcitabine Combined with Fucoidan in Uterine Sarcomas and Carcinosarcoma Cells

Cancers ◽

10.3390/cancers12010107 ◽

2019 ◽

Vol 12 (1) ◽

pp. 107 ◽

Cited By ~ 3

Author(s):

Marcin Bobiński ◽

Karolina Okła ◽

Jarogniew Łuszczki ◽

Wiesława Bednarek ◽

Anna Wawruszak ◽

...

Keyword(s):

Cell Cycle ◽

Synergistic Effect ◽

Cell Line ◽

Cell Lines ◽

Combined Treatment ◽

Endometrial Stromal Sarcoma ◽

Uterine Leiomyosarcoma ◽

Uterine Sarcomas ◽

Isobolographic Analysis ◽

Stromal Sarcoma

Background: Uterine sarcomas and carcinosarcoma are associated with unfavorable prognosis. The regimens that are used in chemotherapy are associated with high incidence of side effects and usually do not significantly increase patients’ survival rates. In this study we investigated the activity and interactions between gemcitabine and fucoidan, the natural compound known for its anti-tumor properties, in human sarcomas and carcinosarcoma cell models. Methods: SK-UT-1, SK-UT1-B (carcinosarcoma), MES-SA (leiomyosarcoma), and ESS-1 (endometrial stromal sarcoma) cell lines were used for the experiments. Cells were incubated in the presence of gemcitabine, fucoidan, and mixtures, after the incubation the MTT tests were performed. In order to assess the interactions between tested compounds isobolographic analysis was performed. Additional assessments of apoptosis and cell cycle were done. Results: Additive effect of combined treatment with gemcitabine and fucoidan was observed in ESS-1 and SK-UT-1 cell line. Although the supra-additive (synergistic) effect noticed in SK-UT-1B cell line. It was not possible to determine the interactions of fucoidan and gemcitabine in MES-SA cell line due to insufficient response to treatment. Addition of fucoidan to gemcitabine enhances its proapoptotic activity, what was observed especially in ESS-1 and SK-UT-1B cell lines. The arrest of cell cycle induced by mixture of gemcitabine and fucoidan, superior comparing gemcitabine alone was observed in SK-UT-1B. Conclusions: Obtained data showed that a combination of fucoidan and gemcitabine in uterine endometrial stromal sarcoma and carcinosarcoma cell lines has additive or even synergistic effect in decreasing cell viability. Furthermore, this drug combination induces apoptosis and arrest of cell cycle. The resistance of uterine leiomyosarcoma cell line, justifies searching for other drugs combinations to improve therapy efficacy.

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The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death

Cancers ◽

10.3390/cancers12010108 ◽

2019 ◽

Vol 12 (1) ◽

pp. 108 ◽

Cited By ~ 1

Author(s):

I-Lun Hsin ◽

Ying-Hsiang Chou ◽

Wei-Li Hung ◽

Jiunn-Liang Ko ◽

Po-Hui Wang

Keyword(s):

Cervical Cancer ◽

Synergistic Effect ◽

Cancer Cells ◽

Arsenic Trioxide ◽

Combination Treatment ◽

Combined Treatment ◽

B Cell Lymphoma ◽

Uterine Cervical Cancer ◽

Cervical Cancer Cells ◽

Mediated Reduction

ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.

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Synergistic effect of aged garlic extract and naltrexone on improving immune responses to experimentally induced fibrosarcoma tumor in BALB/c mice

Pharmacognosy Research ◽

10.4103/0974-8490.112426 ◽

2013 ◽

Vol 5 (3) ◽

pp. 189 ◽

Cited By ~ 6

Author(s):

ManijehYousefi Behzadi ◽

Soheil Ebrahimpour ◽

MohaddesehAbouhosseini Tabari ◽

MohammadReza Youssefi ◽

Hamid Aghajanzadeh

Keyword(s):

Synergistic Effect ◽

Immune Responses ◽

Garlic Extract ◽

Aged Garlic Extract ◽

Aged Garlic ◽

Experimentally Induced

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Correction: Combined Treatment of Xenon and Hypothermia in Newborn Rats - Additive or Synergistic Effect?

PLoS ONE ◽

10.1371/journal.pone.0115986 ◽

2014 ◽

Vol 9 (12) ◽

pp. e115986

Author(s):

Keyword(s):

Synergistic Effect ◽

Combined Treatment ◽

Newborn Rats

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Proton pump inhibitors enhance chemosensitivity, promote apoptosis, and suppress migration of breast cancer cells

Acta Pharmaceutica ◽

10.2478/acph-2020-0020 ◽

2020 ◽

Vol 70 (2) ◽

pp. 179-190 ◽

Cited By ~ 3

Author(s):

Worood G. Ihraiz ◽

Mamoun Ahram ◽

Sanaa K. Bardaweel

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Synergistic Effect ◽

Cancer Cells ◽

Cell Lines ◽

Proton Pump ◽

Breast Cancer Cells ◽

Combined Treatment ◽

Combined Effects ◽

Mcf 7

AbstractBreast cancer is the most common cancer and is the leading cause of cancer deaths among women worldwide. Despite the availability of numerous therapeutics for breast cancer management, cytotoxicity and emergence of drug resistance are major challenges that limit their benefits. The acidic microenvironment surrounding tumor cells is a common feature inducing cancer cell invasiveness and chemoresistance. Proton pump inhibitors (PPIs) are one of the most commonly prescribed drugs for the treatment of acid-related conditions. PPIs have been reported to exhibit antitumorigenic effects in many cancer types. In this study, the anti-proliferative and anti-migratory effects of PPIs in three breast cancer cell lines; MCF-7, T47D, and MDA-MB-231 cells, have been investigated. In addition, the combined effects of PPIs with anticancer drugs, as well as the mechanism of PPI-mediated anti-proliferative activity were evaluated. The anti-proliferative and combined effects of PPIs were evaluated by MTT assay. Cell migration was assessed using the wound-healing assay. The mechanism of cell death was assessed using annexin V-FITC/propidium iodide staining flow cytometry method. Our results indicated that PPIs treatment significantly inhibited the growth of breast cancer cells in a dose-dependent manner. The antiproliferative activity of PPIs was significantly induced by apoptosis in all tested cell lines. The combined treatment of PPIs with doxorubicin resulted in a synergistic effect in all cell lines, whereas the combined treatment with raloxifene exhibited synergistic effect in T47D cells only and additive effects in MDA-MB-231 and MCF-7 cells. In addition, PPIs treatment significantly reduced cell migration in MDA-MB-231 cells. In conclusion, the addition of PPIs to the treatment regimen of breast cancer appears to be a promising strategy to potentiate the efficacy of chemotherapy and may suppress cancer metastasis.

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