scholarly journals Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 869 ◽  
Author(s):  
Tashbib Khan ◽  
Yaowu He ◽  
Thomas Kryza ◽  
Brittney S. Harrington ◽  
Jennifer H. Gunter ◽  
...  
Keyword(s):  
Low Dose ◽  
Clear Cell ◽  
Preclinical Models ◽  
High Stage ◽  
Clear Cell Ovarian Carcinoma ◽  
Xenograft Models ◽  
Glycogen Utilization ◽  
Resistance To Chemotherapy ◽  
Glucose Analogue

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.

scholarly journals Efficacy of the Plk Inhibitor Volasertib in Preclinical Models of AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2307-2307
Author(s):  
Dorothea Rudolph ◽  
Christoph Albrecht ◽  
Lena Geiselmann ◽  
Maria Antonietta Impagnatiello ◽  
Pilar Garin-Chesa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Single Agent ◽  
Preclinical Models ◽  
Subcutaneous Xenograft ◽  
Xenograft Models ◽  
Proliferation Assays ◽  
Anti Tumor Activity

Abstract Background: Polo-like kinase 1 (Plk1), a key regulator of cell cycle progression and accurate spindle assembly, is an attractive target for cancer drug discovery. We have previously shown that volasertib (BI 6727), a potent and selective small-molecule inhibitor of Plk, induces a distinct mitotic arrest phenotype in prometaphase (“polo-arrest”) with subsequent apoptosis in a variety of different cancer cell lines, irrespective of their mutational status. When used in vivo, volasertib administered intravenously shows potent anti-tumor activity in xenograft models of human epithelial cancers at well-tolerated doses. The present study was designed to extend the analysis of volasertib to additional preclinical models of human AML, including bone marrow samples from AML patients. Volasertib is the most advanced Plk inhibitor in clinical development and has demonstrated encouraging results in phase II clinical trials. It is currently being investigated in a phase III clinical trial in patients with previously untreated AML, who are ineligible for intensive remission induction therapy. Methods: A panel of human AML cell lines was used to evaluate pharmacodynamic biomarker modulation and anti-tumor effects of volasertib in vitro using FACS analysis, Western blot analysis and proliferation assays. This in vitro analysis of established AML cell lines was extended to proliferation assays using bone marrow samples from AML patients. In vivo anti-tumor activity of volasertib was tested in subcutaneous xenograft models as well as in multiple disseminated xenograft models of AML. Single-agent efficacy of volasertib and combination therapies were evaluated with existing and emerging AML drugs, including an approved cytotoxic drug (cytarabine), hypomethylating agents (decitabine, azacitidine) and a signal transduction inhibitor targeting FLT3 (quizartinib). Results: Volasertib potently inhibited proliferation of established AML cell lines in vitro with EC50 values of 16-169 nM. Proliferation assays with 15 ex vivo bone marrow samples from AML patients showed EC50 values of 8-8800 nM with a median EC50 of 37 nM. Volasertib showed potent anti-tumor activity at well tolerated doses in 3 subcutaneous xenograft models of AML (MV4-11, Molm-13 and a patient-derived AML model AML-6252). While single-agent volasertib at medium dose level (20 mg/kg q7d i.v. for 2 cycles) and single-agent cytarabine (100 mg/kg q3-4d i.p. for 2 cycles) showed moderate efficacy in the AML-6252 AML model, the combination showed improved efficacy. Moreover, efficacy of single-agent volasertib at high dose level (40 mg/kg q7d i.v. for 2 cycles) could be further improved by adding cytarabine to the treatment regime (Figure 1). A combination of volasertib with decitabine or azacitidine was tested in the MV4-11 subcutaneous AML xenograft model. Either combination therapy showed improved efficacy compared to the respective single-agent treatment groups. Volasertib showed also improved anti-tumor activity when tested in combination with the Flt-3 inhibitor quizartinib (5 or 10 mg/kg qd po for 2 cycles) in the MV4-11 AML model. While tumors in the quizartinib single agent treatment groups started to regrow around day 60 post treatment start, a combination with volasertib could control tumor growth long term until the study was terminated (day 87 post treatment start). Efficacy of volasertib was also tested in 3 disseminated xenograft models of AML (MV4-11, Molm-13 and THP-1). Efficacy read out in these disseminated models was based on tumor load measurements as detected by bioluminescence imaging and increased lifespan. Volasertib prolonged survival compared to vehicle treated animals in all three disseminated models of AML. Conclusions: These results indicate that volasertib is highly efficacious as a single agent in preclinical models of AML and shows potential for improved efficacy and good tolerability in combination with existing and emerging AML drugs. Figure 1: Efficacy of volasertib in combination with cytarabine in a patient-derived AML model (AML-6252) Figure 1:. Efficacy of volasertib in combination with cytarabine in a patient-derived AML model (AML-6252) Disclosures Rudolph: Boehringer Ingelheim RCV: Employment. Off Label Use: Volasertib is an investigational agent. Albrecht:Boehringer Ingelheim RCV GmbH & Co KG: Employment. Geiselmann:Boehringer Ingelheim RCV GmbH & Co KG: Employment. Impagnatiello:Boehringer Ingelheim RCV GmbH & Co KG: Employment. Garin-Chesa:Boehringer Ingelheim RCV: Employment. Wernitznig:Boehringer-Ingelheim: Employment. Moll:Boehringer-Ingelheim: Employment. Kraut:Boehringer Ingelheim RCV: Employment.

Ciamexon in low-dose streptozotocin induced diabetes mellitus. In vivo and in vitro studies

1986 ◽  
Vol 113 (1_Suppl) ◽  
pp. S120-S121
Author(s):  
TH. LINN ◽  
H. GERMANN ◽  
B. HERING ◽  
R. BRETZEL ◽  
K. FEDERLIN
Keyword(s):  
Diabetes Mellitus ◽  
Low Dose ◽  
In Vitro Studies ◽  
Streptozotocin Induced Diabetes

Bioactive Peptides Sensitize Cells to Anticancer Effects of Oxaliplatin in Human Colorectal Cancer Xenografts in Nude Mice

2019 ◽  
Vol 26 (7) ◽  
pp. 512-522
Author(s):  
Xian Li ◽  
Long Xia ◽  
Xiaohui Ouyang ◽  
Qimuge Suyila ◽  
Liya Su ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Nude Mice ◽  
Low Dose ◽  
Bioactive Peptides ◽  
Human Colorectal Cancer ◽  
Short Term ◽  
Hct 116

<P>Background: Despite new agent development and short-term benefits in patients with Colorectal Cancer (CRC), metastatic CRC cure rates have not improved due to high rates of oxaliplatin resistance and toxicity. There is an urgent need for effective tools to prevent and treat CRC and reduce morbidity and mortality of CRC patients. Exploring the effects of bioactive peptides on the antitumor to CRC was of vital importance to the clinical application. </P><P> Objective: This study aimed to investigate the therapeutic impact of Anticancer Bioactive Peptides (ACBP) on anticancer effect of oxaliplatin (LOHP) in human colorectal cancer xenografts models in nude mice. </P><P> Methods: HCT-116 cells were cultured in vitro via CCK-8 assays and the absorbance was measured at 450 nm. Apoptosis and cell cycle were assessed by Flow Cytometry (FCM) in vitro. HCT-116 human colorectal cancer cells inoculated subcutaneously in nude mice of treatment with PBS (GG), ACBP, LOHP, ACBP+LOHP (A+L) in vivo. The quality of life was assessed by dietary amount of nude mice, the weight of nude mice, inhibition rates, tumor weight and tumor volume. Immunohistochemistry and RT-qPCR method was conducted to determine the levels of apoptosisregulating proteins/genes in transplanted tumors. </P><P> Results: ACBP induced substantial reductions in viable cell numbers and apoptosis of HCT116 cells in combined with LOHP in vitro. Compared with the control GG group, ACBP combined low dose oxaliplatin (U) group demonstrated significantly different tumor volume, the rate of apoptosis, the expression levels of Cyt-C, caspase-3,8,9 proteins and corresponding RNAs (P<0.05). The expression of pro-apoptotic proteins in the cytoplasm around the nucleus was significantly enhanced by ACBP. Short term intermittent use of ACBP alone indicted a certain inhibitory effect on tumor growth, and improve the quality of life of tumor bearing nude mice. </P><P> Conclusion: ACBP significantly increased the anti-cancer responses of low dose oxaliplatin (L-LOHP), thus, significantly improving the quality of life of tumor-bearing nude mice.</P>

scholarly journals Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Leukocyte Adhesion ◽  
Endothelial Glycocalyx ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Circulating Levels

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

scholarly journals A Review on the Medicinal and Pharmacological Properties of Traditional Ethnomedicinal Plant Sonapatha, Oroxylum indicum

Sinusitis ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 71-89
Author(s):  
Ganesh Chandra Jagetia
Keyword(s):  
Glucose Transporter ◽  
Skin Diseases ◽  
Regulatory Element ◽  
Experimental Studies ◽  
Fatty Acid Synthetase ◽  
Preclinical Models ◽  
Oroxylin A ◽  
Oroxylum Indicum

Oroxylum indicum, Sonapatha is traditionally used to treat asthma, biliousness, bronchitis, diarrhea, dysentery, fevers, vomiting, inflammation, leukoderma, skin diseases, rheumatoid arthritis, wound injury, and deworm intestine. This review has been written by collecting the relevant information from published material on various ethnomedicinal and pharmacological aspects of Sonapatha by making an internet, PubMed, SciFinder, Science direct, and Google Scholar search. Various experimental studies have shown that Sonapatha scavenges different free radicals and possesses alkaloids, flavonoids, cardio glycosides, tannins, sterols, phenols, saponins, and other phytochemicals. Numerous active principles including oroxylin A, chrysin, scutellarin, baicalein, and many more have been isolated from the different parts of Sonapatha. Sonapatha acts against microbial infection, cancer, hepatic, gastrointestinal, cardiac, and diabetic disorders. It is useful in the treatment of obesity and wound healing in in vitro and in vivo preclinical models. Sonapatha elevates glutathione, glutathione-s-transferase, glutathione peroxidase, catalase, and superoxide dismutase levels and reduces aspartate transaminase alanine aminotransaminase, alkaline phosphatase, lactate dehydrogenase, and lipid peroxidation levels in various tissues. Sonapatha activates the expression of p53, pRb, Fas, FasL, IL-12, and caspases and inhibited nuclear factor kappa (NF-κB), cyclooxygenase (COX-2), tumor necrosis factor (TNFα), interleukin (IL6), P38 activated mitogen-activated protein kinases (MAPK), fatty acid synthetase (FAS), sterol regulatory element-binding proteins 1c (SREBP-1c), proliferator-activated receptor γ2 (PPARγ2), glucose transporter (GLUT4), leptin, and HPV18 oncoproteins E6 and E7 at the molecular level, which may be responsible for its medicinal properties. The phytoconstituents of Sonapatha including oroxylin A, chrysin, and baicalein inhibit the replication of SARS-CoV-2 (COVID-19) in in vitro and in vivo experimental models, indicating its potential to contain COVID-19 infection in humans. The experimental studies in various preclinical models validate the use of Sonapatha in ethnomedicine and Ayurveda.

scholarly journals Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Sungryong Oh ◽  
Joohee Jung
Keyword(s):  
Liver Cancer ◽  
Adverse Effects ◽  
Anticancer Drugs ◽  
Clinical Data ◽  
Xenograft Model ◽  
In Vitro Test ◽  
Incidence And Mortality ◽  
Significant Difference ◽  
Xenograft Models

Abstract Background The incidence and mortality of liver cancer show a great difference between the sexes. We established sex-dependent liver cancer xenograft models and investigated whether such sex-dependent models could be used to simultaneously evaluate the therapeutic and adverse effects of anticancer drugs for drug screening. Results In the in-vitro test, the cytotoxicity of anticancer drugs (cisplatin, 5-fluorouracil, and doxorubicin) was compared between male- and female-derived liver cancer cell lines. Cisplatin and 5-fluorouracil exhibited cytotoxicity without sex-difference, but doxorubicin showed dose-dependently significant cytotoxicity only in male-derived cells. Our results showed a strong correlation between preclinical and clinical data with the use of sex-dependent liver cancer xenograft models. Moreover, the male-derived Hep3B-derived xenograft model was more sensitive than the female-derived SNU-387-derived xenograft model against doxorubicin treatment. Doxorubicin showed more severe cardiotoxicity in the male xenograft model than in the female model. We investigated the occurrence frequency of doxorubicin-related cardiotoxicity using data obtained from the Korea Institute of Drug Safety & Risk Management Database, but no significant difference was observed between the sexes. Conclusions Our results suggest that sex-dependent xenograft models are useful tools for evaluating the therapeutic and adverse effects of anticancer drugs, because sex is an important consideration in drug development.

scholarly journals The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3470
Author(s):  
Aubrey L. Miller ◽  
Patrick L. Garcia ◽  
Samuel C. Fehling ◽  
Tracy L. Gamblin ◽  
Rebecca B. Vance ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cholesterol Biosynthesis ◽  
Antitumor Efficacy ◽  
Rna Seq ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Xenograft Models

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.

Comparison of surgical and oncologic outcomes in patients with clear cell ovarian carcinoma associated with and without endometriosis

2021 ◽  
Author(s):  
Ruja Charatsingha ◽  
Suchanan Hanamornroongruang ◽  
Mongkol Benjapibal ◽  
Suwanit Therasakvichya ◽  
Atthapon Jaishuen ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Clear Cell ◽  
Oncologic Outcomes ◽  
Clear Cell Ovarian Carcinoma
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