Proapoptotische Strategien gegen Melanomzellen

Zusammenfassung

Die Apoptose stellt einen grundlegenden Mechanismus zur Aufrechterhaltung der zellulären Homöostase dar. Intrinsische proapoptotische Signalwege werden durch p53 induziert und greifen insbesondere auf der Ebene der Mitochondrien an. Demgegenüber basiert die extrinsische Induktion der Apoptose maßgeblich auf der Bindung von Todesliganden (TNF-alpha, CD95L/FasL, TRAIL) an ihre Rezeptoren sowie auf der Induktion der Caspasen-Kaskade. Für die Tumorprogression sowie für die Therapieresistenz maligner Tumoren ist die Inaktivierung proapoptotischer Signalwege eine notwendige Voraussetzung. So wurden auch verschiedene Mechanismen der Apoptoseresistenz für das im hohen Maße therapieresistente maligne Melanom identifiziert. Ziel verschiedener neuer Therapiekonzepte gegen Krebs ist daher insbesondere die Überwindung dieser Apoptoseresistenz, wobei Todesliganden wichtige Hoffnungsträger darstellen. Insbesondere TRAIL (TNF-related apoptosis-inducing ligand) hat aufgrund seiner hohen selektiven Effektivität gegen Tumorzellen bereits Eingang in klinische Studien gefunden. Das maligne Melanom war hierbei allerdings bisher weitgehend ausgeschlossen. TRAIL bindet an die zwei agonistischen Todesrezeptoren TRAIL-R1/DR4 und TRAIL-R2/DR5. Neue Befunde an Melanomzelllinien und Biopsien von Melanom-Primärtumoren zeigten, dass TRAIL in Melanomzellen über DR4 sehr effizient Apoptose induzieren kann und dass die Mehrzahl der Primärmelanome den DR4 stark exprimieren. Apoptose-gestützte Strategien stellen einen wichtigen Schritt zur Entwicklung effektiver Tumortherapien dar, und TRAIL könnte sich zu einer viel versprechenden Therapieoption auch beim malignen Melanom entwickeln.

Abstract

Apoptosis represents a basic mechanism for maintenance of cellular homeostasis. Intrinsic proapoptotic pathways are induced by p53 and employ especially the mitochondrial level. In contrast, the extrinsic induction of apoptosis is based on the binding of death ligands (TNF-alpha, CD95L/FasL, TRAIL) to their respective receptors and on induction of the caspase cascade. For tumor progression and for therapy resistance of malignant tumors, the inactivation of proapoptotic pathways is a prerequisite. Thus, several mechanisms of apoptosis resistance have been identified for the highly therapy resistant malignant melanoma. Therefore many new anti-cancer concepts aim especially to overcome this apoptosis resistance, and death ligands may supply promising strategies. Especially with TRAIL (TNF-related apoptosis-inducing ligand) several clinical studies have been initiated because of its high and selective efficiency against tumor cells. However, these studies so far largely excluded melanoma. TRAIL binds the two agonistic death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. New data on melanoma cell lines and biopsies revealed that TRAIL can efficiently induce apoptosis in melanoma cells via DR4, and the majority of primary melanomas do express DR4. Apoptosis-based strategies represent an important step in development of tumor therapies, and TRAIL may evolve into a promising therapeutic option also for melanoma.

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