12142
2014
eng
4799-810
13
5
article
1
2015-10-29
--
--
Enhanced Orai1 and STIM1 expression as well as store operated \(Ca^{2+}\) entry in therapy resistant ovary carcinoma cells
Mechanisms underlying therapy resistance of tumor cells include protein kinase Akt. Putative Akt targets include store-operated \(Ca^{2+}\)-entry (SOCE) accomplished by pore forming ion channel unit Orai1 and its regulator STIM1. We explored whether therapy resistant (A2780cis) differ from therapy sensitive (A2780) ovary carcinoma cells in Akt, Orai1, and STIM1 expression, \(Ca^{2+}\)-signaling and cell survival following cisplatin (100µM) treatment. Transcript levels were quantified with RT-PCR, protein abundance with Western blotting, cytosolic \(Ca^{2+}\)-activity ([\(Ca^{2+}\)]i) with Fura-2-fluorescence, SOCE from increase of [\(Ca^{2+}\)]i following \(Ca^{2+}\)-readdition after Ca2+-store depletion, and apoptosis utilizing flow cytometry. Transcript levels of Orai1 and STIM1, protein expression of Orai1, STIM1, and phosphorylated Akt, as well as SOCE were significantly higher in A2780cis than A2780 cells. SOCE was decreased by Akt inhibitor III (SH-6, 10µM) in A2780cis but not A2780 cells and decreased in both cell lines by Orai1 inhibitor 2-aminoethoxydiphenyl borate (2-ABP, 50µM). Phosphatidylserine exposure and late apoptosis following cisplatin treatment were significantly lower in A2780cis than A2780 cells, a difference virtually abolished by SH-6 or 2-ABP. In conclusion, Orai1/STIM1 expression and function are increased in therapy resistant ovary carcinoma cells, a property at least in part due to enhanced Akt activity and contributing to therapy resistance in those cells.
Oncotarget
25015419
www.impactjournals.com/oncotarget
urn:nbn:de:bvb:20-opus-121423
Oncotarget, Vol. 5, No. 13, p. 4799-810
Sebastian Schmidt
Guoxing Liu
Guilai Liu
Wenting Yang
Sabina Honisch
Stavros Pantelakos
Christos Stournaras
Arnd Hönig
Florian Lang
eng
uncontrolled
Ca2+ release activated Ca2+ channel
eng
uncontrolled
SOCE
eng
uncontrolled
Akt
eng
uncontrolled
SH-6
eng
uncontrolled
2-APB
eng
uncontrolled
apoptosis
Medizin und Gesundheit
open_access
Frauenklinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12142/048_Schmidt_Oncotarget.pdf
12001
2014
eng
129–139
2
6
article
1
2015-10-08
--
--
Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion
The ectonucleotidases CD39 and CD73 degrade ATP to adenosine which inhibits immune responses via the \(A_{2A}\) adenosine receptor (ADORA2A) on T and NK cells. The current study investigates the potential therapeutic use of the specific anti CD39- and anti CD73-antibodies A1 (CD39) and 7G2 (CD73) as these two ectonucleotidases are overexpressed in ovarian cancer (OvCA). As expected, NK cell cytotoxicity against the human ovarian cancer cell lines OAW-42 or SK-OV-3 was significantly increased in the presence of A1 or 7G2 antibody. While this might partly be due to antibody-dependent cell-mediated cytotoxicity, a luciferase-dependent assay for quantifying biologically active adenosine further showed that A1 and 7G2 can inhibit CD39 and CD73-dependent adenosine-generation. In turn, the reduction in adenosine levels achieved by addition of A1 and 7G2 to OAW-42 or SK-OV-3 cells was found to de-inhibit the proliferation of \(CD4^+\) T cells in coculture with OvCA cells. Likewise, blocking of CD39 and CD73 on OvCA cells via A1 and 7G2 led to an increased cytotoxicity of alloreactive primed T cells. Thus, antibodies like A1 and 7G2 could improve targeted therapy in ovarian cancer not only by specifically labeling overexpressed antigens but also by blocking adenosine-dependent immune evasion in this immunogenic malignancy.
American Journal of Translational Research
1943-8141
PMC3902223
urn:nbn:de:bvb:20-opus-120016
American Journal of Translational Research 2014;6(2):129-139
Sebastian F. M. Häusler
Itsaso Montalbán del Barrio
Joachim Diessner
Roland G. Stein
Jenny Strohschein
Arnd Hönig
Johannes Dietl
Jörg Wischhusen
eng
uncontrolled
ovarian cancer
eng
uncontrolled
immune escape
eng
uncontrolled
adenosine
eng
uncontrolled
CD39
eng
uncontrolled
CD73
Gynäkologie, Geburtsmedizin, Pädiatrie, Geriatrie
open_access
Frauenklinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12001/070_Haeusler_AMERICAN_JOURNAL_OF_TRANSLATIONAL_RESEARCH.pdf
12863
2013
eng
221-220
2
3
article
1
2016-03-04
--
--
Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells
Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of \(CD44^{high}CD24^{low}HER2^{low}\) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.
American Journal of Cancer Research
urn:nbn:de:bvb:20-opus-128633
American Journal of Cancer Research 2013;3(2):211-220
Joachim Diessner
Valentin Bruttel
Kathrin Becker
Miriam Pawlik
Roland Stein
Sebastian Häusler
Johannes Dietl
Jörg Wischhusen
Arnd Hönig
eng
uncontrolled
trastuzumab
eng
uncontrolled
breast cancer
eng
uncontrolled
tumor stem cells
eng
uncontrolled
ADCC
eng
uncontrolled
pertuzumab
Medizin und Gesundheit
open_access
Frauenklinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12863/007_Diessner_Targeting_breast_cancer.pdf
9626
2013
eng
article
1
--
--
--
Must we press on until a young mother dies? Remifentanil patient controlled analgesia in labour may not be suited as a “poor man’s epidural”
Background
The epidural route is still considered the gold standard for labour analgesia, although it is not without serious consequences when incorrect placement goes unrecognized, e.g. in case of intravascular, intrathecal and subdural placements. Until now there has not been a viable alternative to epidural analgesia especially in view of the neonatal outcome and the need for respiratory support when long-acting opioids are used via the parenteral route. Pethidine and meptazinol are far from ideal having been described as providing rather sedation than analgesia, affecting the cardiotocograph (CTG), causing fetal acidosis and having active metabolites with prolonged half-lives especially in the neonate. Despite these obvious shortcomings, intramuscular and intravenously administered pethidine and comparable substances are still frequently used in delivery units.
Since the end of the 90ths remifentanil administered in a patient-controlled mode (PCA) had been reported as a useful alternative for labour analgesia in those women who either don’t want, can’t have or don’t need epidural analgesia.
Discussion
In view of the need for conversion to central neuraxial blocks and the analgesic effect remifentanil has been demonstrated to be superior to pethidine. Despite being less effective in terms of the resulting pain scores, clinical studies suggest that the satisfaction with analgesia may be comparable to that obtained with epidural analgesia. Owing to this fact, remifentanil has gained a place in modern labour analgesia in many institutions.
However, the fact that remifentanil may cause harm should not be forgotten when the use of this potent mu-agonist is considered for the use in labouring women. In the setting of one-to-one midwifery care, appropriate monitoring and providing that enough experience exists with this potent opioid and the treatment of potential complications, remifentanil PCA is a useful option in addition to epidural analgesia and other central neuraxial blocks. Already described serious consequences should remind us not refer to remifentanil PCA as a “poor man’s epidural” and to safely administer remifentanil with an appropriate indication.
Summary
Therefore, the authors conclude that economic considerations and potential cost-savings in conjunction with remifentanil PCA may not be appropriate main endpoints when studying this valuable method for labour analgesia.
BMC Pregnancy and Childbirth
10.1186/1471-2393-13-139
http://www.biomedcentral.com/1471-2393/13/139
urn:nbn:de:bvb:20-opus-96262
In: BMC Pregnancy and Childbirth (2013) 13: 139, doi:10.1186/1471-2393-13-139
Peter Kranke
Thierry Girard
Patricia Lavand’homme
Andrea Melber
Johanna Jokinen
Ralf M. Muellenbach
Johannes Wirbelauer
Arnd Hönig
eng
uncontrolled
Remifentanil
eng
uncontrolled
Epidural Analgesia
eng
uncontrolled
Labour Pain
eng
uncontrolled
Labour Analgesia
eng
uncontrolled
Patient Controlled Analgesia
eng
uncontrolled
Patient Satisfaction
eng
uncontrolled
Healthcare Cost
eng
uncontrolled
Healthcare Economics
Medizin und Gesundheit
open_access
Frauenklinik und Poliklinik
Kinderklinik und Poliklinik
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9626/Kranke_1471-2393-13-139.pdf