scholarly journals Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

2019 ◽  
Vol 21 (1) ◽  
pp. 252 ◽  
Author(s):  
Elisabeth M. Haberl ◽  
Rebekka Pohl ◽  
Lisa Rein-Fischboeck ◽  
Susanne Feder ◽  
Christopher J. Sinal ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Ex Vivo ◽  
Liver Steatosis ◽  
Tumor Burden ◽  
Fibrotic Liver ◽  
Adeno Associated Virus ◽  
Highly Active ◽  
Lipid Species ◽  
Inhibitory Potential ◽  
Coenzym A

The tumor inhibitory potential of the highly active chemerin-156 isoform was described in orthotopic models of hepatocellular carcinoma (HCC). The majority of HCC arises in the fibrotic liver, which was not reproduced in these studies. Here, a potential therapeutic activity of chemerin-156 was evaluated in diethylnitrosamine (DEN)-induced liver cancer, which mimics fibrosis-associated HCC. Mice were infected with adeno-associated virus (AAV) six months after DEN injection to overexpress chemerin-156 in the liver, and animals injected with non-recombinant-AAV served as controls. Three months later, the animals were killed. Both groups were comparable with regard to liver steatosis and fibrosis. Of note, the number of very small tumors was reduced by chemerin-156. Anyhow, the expression of inflammatory and profibrotic genes was similar in larger tumors of control and chemerin-156-AAV-infected animals. Although genes with a role in lipid metabolism, like 3-hydroxy-3-methylglutaryl-coenzym-A--reductase, were overexpressed in tumors of animals with high chemerin-156, total hepatic cholesterol, diacylglycerol and triglyceride levels, and distribution of individual lipid species were normal. Chemerin-156-AAV-infected mice had elevated hepatic and systemic chemerin. Ex vivo activation of the chemerin receptor chemokine-like receptor 1 increased in parallel with serum chemerin, illustrating the biological activity of the recombinant protein. In the tumors, chemerin-155 was the most abundant variant. Chemerin-156 was not detected in tumors of the controls and was hardly found in chemerin-156-AAV infected animals. In conclusion, the present study showed that chemerin-156 overexpression caused a decline in the number of small lesions but did not prevent the growth of pre-existing neoplasms.

scholarly journals Adeno-Associated Virus Type 2 and Hepatocellular Carcinoma?

2015 ◽  
Vol 26 (12) ◽  
pp. 779-781 ◽  
Author(s):  
Kenneth I. Berns ◽  
Barry J. Byrne ◽  
Terence R. Flotte ◽  
Guangping Gao ◽  
William W. Hauswirth ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Virus Type ◽  
Adeno Associated Virus

scholarly journals Ex vivo and in vitro inhibitory potential of Kava extract on monoamine oxidase B activity in mice

2021 ◽  
Author(s):  
Bárbara Nunes Krum ◽  
Catiuscia Molz de Freitas ◽  
Alcindo Busanello ◽  
Larissa Finger Schaffer ◽  
Roselei Fachinetto
Keyword(s):  
Monoamine Oxidase ◽  
Ex Vivo ◽  
Monoamine Oxidase B ◽  
Inhibitory Potential

Analysis of adeno-associated virus-mediated ex vivo transferred human β-globin gene in bone marrow engrafted mice

2002 ◽  
Vol 9 (3) ◽  
pp. 253-260
Author(s):  
Wen-Ji Dong ◽  
Xiao-Bing Wu ◽  
De-Pei Liu ◽  
Jia Li ◽  
Guang Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Globin Gene ◽  
Adeno Associated Virus

scholarly journals Human GDPD3 overexpression promotes liver steatosis by increasing lysophosphatidic acid production and fatty acid uptake

2020 ◽  
Vol 61 (7) ◽  
pp. 1075-1086 ◽  
Author(s):  
Chia-Chi C. Key ◽  
Andrew C. Bishop ◽  
Xianfeng Wang ◽  
Qingxia Zhao ◽  
Guan-yuan Chen ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Liver Steatosis ◽  
Fatty Acid Uptake ◽  
Western Diet ◽  
Acid Uptake ◽  
Mrna Levels ◽  
Glycerol Phosphate ◽  
Adeno Associated Virus ◽  
Mouse Hepatocytes ◽  
Tag Accumulation

The glycerol phosphate pathway produces more than 90% of the liver triacylglycerol (TAG). LysoPA, an intermediate in this pathway, is produced by glycerol-3-phosphate acyltransferase. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), whose gene was recently cloned, contains lysophospholipase D activity, which produces LysoPA from lysophospholipids. Whether human GDPD3 plays a role in hepatic TAG homeostasis is unknown. We hypothesized that human GDPD3 increases LysoPA production and availability in the glycerol phosphate pathway, promoting TAG biosynthesis. To test our hypothesis, we infected C57BL/6J mice with adeno-associated virus encoding a hepatocyte-specific albumin promoter that drives GFP (control) or FLAG-tagged human GDPD3 overexpression and fed the mice chow or a Western diet to induce hepatosteatosis. Hepatic human GDPD3 overexpression induced LysoPA production and increased FA uptake and incorporation into TAG in mouse hepatocytes and livers, ultimately exacerbating Western diet-induced liver steatosis. Our results also showed that individuals with hepatic steatosis have increased GDPD3 mRNA levels compared with individuals without steatosis. Collectively, these findings indicate that upregulation of GDPD3 expression may play a key role in hepatic TAG accumulation and may represent a molecular target for managing hepatic steatosis.

scholarly journals Newly developed dual topoisomerase inhibitor P8-D6 is highly active in ovarian cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110598
Author(s):  
Inken Flörkemeier ◽  
Tamara N. Steinhauer ◽  
Nina Hedemann ◽  
Magnus Ölander ◽  
Per Artursson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Topoisomerase I ◽  
Ex Vivo ◽  
Chemotherapy Resistance ◽  
Membrane Integrity ◽  
Three Dimensional ◽  
New Drugs ◽  
Highly Active ◽  
Gynaecologic Neoplasms

Background: Ovarian cancer (OvCa) constitutes a rare and highly aggressive malignancy and is one of the most lethal of all gynaecologic neoplasms. Due to chemotherapy resistance and treatment limitations because of side effects, OvCa is still not sufficiently treatable. Hence, new drugs for OvCa therapy such as P8-D6 with promising antitumour properties have a high clinical need. The benzo[ c]phenanthridine P8-D6 is an effective inductor of apoptosis by acting as a dual topoisomerase I/II inhibitor. Methods: In the present study, the effectiveness of P8-D6 on OvCa was investigated in vitro. In various OvCa cell lines and ex vivo primary cells, the apoptosis induction compared with standard therapeutic agents was determined in two-dimensional monolayers. Expanded by three-dimensional and co-culture, the P8-D6 treated cells were examined for changes in cytotoxicity, apoptosis rate and membrane integrity via scanning electron microscopy (SEM). Likewise, the effects of P8-D6 on non-cancer human ovarian surface epithelial cells and primary human hepatocytes were determined. Results: This study shows a significant P8-D6-induced increase in apoptosis and cytotoxicity in OvCa cells which surpasses the efficacy of well-established drugs like cisplatin or the topoisomerase inhibitors etoposide and topotecan. Non-cancer cells were affected only slightly by P8-D6. Moreover, no hepatotoxic effect in in vitro studies was detected. Conclusion: P8-D6 is a strong and rapid inductor of apoptosis and might be a novel treatment option for OvCa therapy.

scholarly journals Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 427
Author(s):  
Nadja Meumann ◽  
Christian Schmithals ◽  
Leroy Elenschneider ◽  
Tanja Hansen ◽  
Asha Balakrishnan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Tissue ◽  
Transduction Efficiency ◽  
Mouse Tumor ◽  
Mechanistic Studies ◽  
Human Patient ◽  
Adeno Associated Virus ◽  
Efficient Delivery ◽  
Stage Disease ◽  
Natural Target

Although therapeutic options are gradually improving, the overall prognosis for patients with hepatocellular carcinoma (HCC) is still poor. Gene therapy-based strategies are developed to complement the therapeutic armamentarium, both in early and late-stage disease. For efficient delivery of transgenes with antitumor activity, vectors demonstrating preferred tumor tropism are required. Here, we report on the natural tropism of adeno-associated virus (AAV) serotype 2 vectors for HCC. When applied intravenously in transgenic HCC mouse models, similar amounts of vectors were detected in the liver and liver tumor tissue. In contrast, transduction efficiency, as indicated by the level of transgene product, was moderate in the liver but was elevated up to 19-fold in mouse tumor tissue. Preferred transduction of HCC compared to hepatocytes was confirmed in precision-cut liver slices from human patient samples. Our mechanistic studies revealed that this preference is due to the improved intracellular processing of AAV2 vectors in HCC, resulting, for example, in nearly 4-fold more AAV vector episomes that serve as templates for gene transcription. Given this background, AAV2 vectors ought to be considered to strengthen current—or develop novel—strategies for treating HCC.

scholarly journals Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 337
Author(s):  
John D. Christie ◽  
Nicole Appel ◽  
Liqiang Zhang ◽  
Kenneth Lowe ◽  
Jacquelyn Kilbourne ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Ex Vivo ◽  
Tumor Burden ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Systemic Delivery ◽  
Clinical Cancer Research ◽  
Critical Issues

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

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