Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53

المؤلفون المشاركون

Kollmeier, Jens
Borchert, Sabrina
Wessolly, Michael
Hager, Thomas
Eberhardt, Wildfried E. E.
Wohlschlaeger, Jeremias
Bankfalvi, Agnes
Schmid, Kurt Werner
Mairinger, Fabian D.
Walter, Robert F. H.
Werner, Robert
Mairinger, Elena
Schmeller, Jan
Mairinger, Thomas
Christoph, Daniel C.
Plönes, Till
Aigner, Clemens

المصدر

Journal of Oncology

العدد

المجلد 2018، العدد 2018 (31 ديسمبر/كانون الأول 2018)، ص ص. 1-10، 10ص.

الناشر

Hindawi Publishing Corporation

تاريخ النشر

2018-07-17

دولة النشر

مصر

عدد الصفحات

10

التخصصات الرئيسية

الأمراض
الطب البشري

الملخص EN

Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival.

A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence.

It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells.

Nutlin-3A (a cis-imidazoline analogue) has been described as a potent and selective MDM2 inhibitor preventing MDM2-TP53-interaction by specific binding to the hydrophobic TP53-binding pocket of MDM2.

In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2—P14/ARF.

Our in vitro experiments on MPM cell lines revealed that Nutlin-3A in combination with cisplatin resulted in up to 9.75 times higher induction of senescence (p=0.0050) and up to 5 times higher apoptosis rate (p=0.0067) compared to the commonly applied cisplatin and pemetrexed regimens.

Thus Nutlin-3A, a potent inhibitor of MDM2, is associated with a significant induction of senescence and apoptosis in MPM cell lines, making Nutlin-3A a promising substance for a targeted therapy in the subgroup of MPM showing MDM2 overexpression.

نمط استشهاد جمعية علماء النفس الأمريكية (APA)

Walter, Robert F. H.& Werner, Robert& Wessolly, Michael& Mairinger, Elena& Borchert, Sabrina& Schmeller, Jan…[et al.]. 2018. Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53. Journal of Oncology،Vol. 2018, no. 2018, pp.1-10.
https://search.emarefa.net/detail/BIM-1195749

نمط استشهاد الجمعية الأمريكية للغات الحديثة (MLA)

Walter, Robert F. H.…[et al.]. Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53. Journal of Oncology No. 2018 (2018), pp.1-10.
https://search.emarefa.net/detail/BIM-1195749

نمط استشهاد الجمعية الطبية الأمريكية (AMA)

Walter, Robert F. H.& Werner, Robert& Wessolly, Michael& Mairinger, Elena& Borchert, Sabrina& Schmeller, Jan…[et al.]. Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53. Journal of Oncology. 2018. Vol. 2018, no. 2018, pp.1-10.
https://search.emarefa.net/detail/BIM-1195749

نوع البيانات

مقالات

لغة النص

الإنجليزية

الملاحظات

Includes bibliographical references

رقم السجل

BIM-1195749