Untersuchungen zur TRAIL-induzierten Apoptose von Ovarialkarzinomzelllinien mit selektiver Zytostatikaresistenz

Meinhold‐Heerlein, Ivo; Borges-Engeby, K.; Grünn, U.; Bauerschlag, Dirk; Maass, N; Mundhenke, Christoph; Jonat, W.; Bauknecht, Thomas

doi:10.1055/s-2005-872998

Cited by 4 publications

(2 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CRYAB‐ or vector‐transfected OV‐MZ‐6 and HEY cells, respectively, were cultivated for 24 h and thereafter incubated with soluble human recombinant TRAIL (KillerTRAIL, Enzo Life Sciences) (0, 3, or 15 ng/ml) or cisplatin (0, 2.5, 5, or 8 μg/ml) or cisplatin (2.5 μg/ml) in combination with TRAIL (3 ng/ml) for another 24 h. The concentration ranges for TRAIL as well as cisplatin treatment, used in the present study, were adopted according to previously published experiments performed by Meinhold‐Heerlein et al 27. on HEY cells.…”

Section: Methodsmentioning

confidence: 99%

High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL‐ and cisplatin‐induced apoptosis in human ovarian cancer cells

Volkmann

Reuning

Rudelius³

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin aB (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p 5 0.001, recurrence-free survival (RFS) p 5 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR 5 2.11, 95% CI 1.10-4.06) and RFS (HR 5 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001) . Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL-as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anticancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from TRAIL-containing therapy.Epithelial ovarian cancer is the fifth most common cause for cancer-related death in women in Western societies and has the highest relative mortality among gynecological cancers. 1,2Approximately 75% of patients are diagnosed at an advanced FIGO stage (III or IV). These patients display a 5-year survival rate of less than 40%.1,3 The currently recommended standard postoperative chemotherapy is platinum-taxanebased. Although initial response rates are often high, most of the patients relapse and develop chemoresistance with fatal outcome. 4 Besides decreased response to DNA damage, increased tumor cell survival largely mediated through dysregulation of apoptotic pathways is regarded as one major reason for chemoresistance. 5,6 This prompted us to search for molecular factors affecting apoptotic pathways in human ovarian cancer, and consequently, patient survival.Differential mRNA expression analysis in tumor specimens of a clinically homogenous cohort of 103 human ovarian cancer patients disclosed CRYAB, a member of the highly

show abstract

Section: Methodsmentioning

confidence: 99%

High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL‐ and cisplatin‐induced apoptosis in human ovarian cancer cells

Volkmann

Reuning

Rudelius³

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Verschiedene Mechanismen der Chemotherapieresistenz konnten mittels neuer molekularbiologischer Techniken in den letzten Jahren identifiziert werden [95]. Insbesondere spielen die sog.…”

Section: Resistenzmodulatorenunclassified

Aktuelle Aspekte der Therapie des platinresistenten Ovarialkarzinoms

Sehouli¹,

Pîrvulescu²,

Mustea³

et al. 2007

Geburtsh Frauenheilk

View full text Add to dashboard Cite

Bei einer Inzidenz von 14 pro 100 000 erkranken jährlich in Deutschland etwa 8000 Frauen an einem Ovarialkarzinom, wobei ca. 6000 Frauen pro Jahr an dieser Erkrankung versterben. Mindestens 75% der Patientinnen weisen zum Zeitpunkt der Diagnose bereits ein fortgeschrittenes Tumorstadium mit Nachweis extrapelviner Metastasen (FIGO III/IV) auf [31]. Dies wird zu einem auf die erst spät einsetzende und unspezifische Symptomatik und dem Fehlen eines effektiven Screenings zurückgeführt. Als Goldstandard des klinischen Managements von Patientinnen mit fortgeschrittenem Ovarialkarzinom gilt in der Primärsituation die maximale Tumorentfernung bzw.-reduktion und eine anschließende Chemotherapie mit Paclitaxel und Carboplatin [10, 40]. Das Ovarialkarzinom gehört zwar zu den chemotherapiesensibelsten soliden Tumoren überhaupt, doch entwickeln mehr als 50 % der Patientinnen mit klinischer Komplettremission ein Rezidiv, das 5-Jahres-Überleben der Stadien III/IV beträgt nur ca. 25% [48]. Die Chemotherapieresistenz (definiert durch die GOG, l " Tab. 1), stellt ein besonderes klinisches Problem für die Patientinnen dar, welches durch folgende Besonderheiten charakterisiert ist: " Häufige Präsenz tumorbedingter Symptome (z. B. Subileus, Aszites). Zusammenfassung ! Die Operation mit dem Ziel der maximalen Tumorreduktion gefolgt von einer systemischen Chemotherapie mit Paclitaxel und Carboplatin sind die entscheidenden Therapieschritte im Management von fortgeschrittenem Ovarialkarzinom. Trotz der hohen Ansprechraten auf die Chemotherapie rezidiviert der Großteil der Patientinnen. Für die Therapiewahl in der Rezidivsituation ist besonders das therapiefreie Intervall von Relevanz. Für Patientinnen mit einem platinresistenten Ovarialkarzinom werden zwar verschiedene Therapiemodalitäten wie Chemotherapie und Hormontherapie eingesetzt, die Ansprechraten sind jedoch sehr unbefriedigend. Auf Basis von publizierten Studien und aktueller Leitlinien werden die einzelnen Therapieoptionen diskutiert und auch neue zielgerichtete Therapieansätze vorgestellt.

show abstract

Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

et al. 2011

View full text Add to dashboard Cite

BackgroundTumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis.MethodsFDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis.ResultsFourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells.ConclusionsThe identification of a number of FDA-approved drugs as TRAIL sensitizers can expand chemotherapeutic options for combination treatments in prostate and pancreatic cancer diseases.

show abstract

Untersuchungen zur TRAIL-induzierten Apoptose von Ovarialkarzinomzelllinien mit selektiver Zytostatikaresistenz

Cited by 4 publications

References 16 publications

High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL‐ and cisplatin‐induced apoptosis in human ovarian cancer cells

High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL‐ and cisplatin‐induced apoptosis in human ovarian cancer cells

Aktuelle Aspekte der Therapie des platinresistenten Ovarialkarzinoms

Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

Contact Info

Product

Resources

About