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Int. J. Mol. Sci. 2015, 16(2), 4190-4208;

The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Hoppe-Seyler-Strasse 1, Tübingen D-72076, Germany
Author to whom correspondence should be addressed.
Academic Editor: Johannes Haybaeck
Received: 29 November 2014 / Revised: 1 February 2015 / Accepted: 9 February 2015 / Published: 16 February 2015
(This article belongs to the Collection Molecular Mechanisms of Human Liver Diseases)
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Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance and occurrence of metastases remain the major challenges in the treatment of HB, especially in high-risk tumors. These conditions urgently require the development of alternative therapeutic strategies. One of those alternatives is the modulation of apoptosis in HB cells. HBs regularly overexpress anti-apoptotic proteins of the Bcl-family in comparison to healthy liver tissue. This fact may contribute to the development of chemoresistance of HB cells. Synthetic small inhibitory molecules with BH3-mimetic effects, such as ABT-737 and obatoclax, enhance the susceptibility of tumor cells to different cytotoxic drugs and thereby affect initiator proteins of the apoptosis cascade via the intrinsic pathway. Besides additive effects on HB cell viability when used in combination with cytotoxic drugs, BH3-mimetics also play a role in preventing metastasation by reducing adhesion and inhibiting cell migration abilities. Presumably, including additive BH3-mimetic drugs into existing therapeutic regimens in HB patients might allow dose reduction of established cytotoxic drugs and thereby associated immanent side effects, while maintaining the antitumor activity. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may facilitate complete surgical tumor resection, which is mandatory in this tumor type resulting in improved survival rates in high-risk HB. Currently, there are phase I and phase II clinical trials in several cancer entities using this potential target. This paper reviews the available literature regarding the use of BH3-mimetic drugs as single agents or in combination with chemotherapy in various malignancies and focuses on results in HB cells. View Full-Text
Keywords: pediatric hepatoblastoma; multi drug resistance; metastases; modulation of apoptosis; BH3-mimetic drugs; ABT-737; obatoclax pediatric hepatoblastoma; multi drug resistance; metastases; modulation of apoptosis; BH3-mimetic drugs; ABT-737; obatoclax

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Lieber, J.; Armeanu-Ebinger, S.; Fuchs, J. The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma. Int. J. Mol. Sci. 2015, 16, 4190-4208.

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