Ein neuer Akt in der Tumortherapie? Inhibition des PI3K/Akt-Kinasewegs als neue Therapieoption bei Tumorerkrankungen

Zusammenfassung

Die Proteinkinase Akt/PKB (Proteinkinase B) nimmt in ihrer aktivierten Form als Bestandteil des PI3K/Akt-Signaltransduktionswegs, der durch Stimulation zahlreicher Wachstumsfaktorrezeptoren stimuliert wird, eine zentrale Rolle als antiapoptotischer, proliferationsfördernder Signalvermittler ein. Die durch Phosphorylierung aktivierte Akt-Kinase phosphoryliert ihrerseits eine Vielzahl von Zielmolekülen, die so unterschiedliche Funktionen wie Überleben und Proliferation, Stoffwechselprozesse, Zellgröße, Angiogenese und Resistenz gegenüber Sauerstoffmangel regeln. In Tumoren ist der PI3K/Akt-Weg häufig dereguliert und eine aberrante Aktivierung von Akt resultiert in der Blockade von Apoptose, Förderung der Proliferation, Neoangiogenese, einem in der Regel fortgeschrittenen und aggressiven Phänotyp sowie Resistenz gegenüber zytotoxischer Behandlung. Der PI3K/Akt-Weg ist folglich eine wichtige Zielstruktur für therapeutische Interventionen. Neben bekannten inhibitorischen Substanzen, die experimentell eingesetzt werden, aber den Weg in die Klinik bislang nicht gefunden haben, wird zurzeit eine Vielzahl von Verbindungen getestet, die entweder oberhalb von Akt/PKB ansetzen, Akt/PKB direkt inhibieren oder in nachgeschaltete Prozesse eingreifen. Die vielfältigen Funktionen von Akt/PKB machen es dabei erforderlich, Substanzen und/oder Dosen zu finden, die möglichst tumorselektiv wirksam und nebenwirkungsfrei sind. Der vorliegende Übersichtsartikel zeigt eine Reihe neuerer Entwicklungen auf diesem Gebiet auf.

Abstract

The protein kinase Akt (also known as protein kinase B, PKB) as part of the PI3K/Akt signal transduction pathway stimulated by a number of growth factor receptors in its activated form plays a crucial role as an antiapoptotic and proliferation-inducing molecule. Phospho-Akt as activated form phosphorylates a plethora of target molecules involved in regulation of survival and proliferation, cell metabolism and cell size regulation, angiogenesis, and resistance to hypoxia. Deregulation of the PI3K/Akt signal cascade is a hallmark of many human tumors and indicative of late stage, an aggressive phenotype as well as resistance to cytotoxic treatment. Thus, the PI3K/Akt pathway is an obvious target for therapeutic intervention. Apart from substances widely used in experimental settings that have not found their way to the clinics yet a multitude of new candidate inhibitors acting either upstream of Akt, inhibiting Akt itself or being effective downstream of Akt are evaluated. The multifarious activities of Akt also in normal cells require special qualities of the substances themselves or their dosages to procure the highest tumor selectivity possible. This review briefly summarizes actual developments in this exciting field.

Gezielte Tumortherapie - PI3K/Akt - Signalweg - neue Substanzen

Targeted tumor therapy - PI3K/Akt - pathway - novel drug candidates

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