Proteasomeninhibitoren: Apoptoseinduktion als neue Therapieoption beim Prostatakarzinom?

Zusammenfassung

„Molecular targeting” gewinnt auch bei der Suche nach neuen Therapiekonzepten für das Prostatakarzinom durch zunehmendes Wissen um die molekulare Pathogenese an Bedeutung [29] [35]. Ein solches Targeting scheint besonders mit Proteasomeninhibitoren möglich. Proteasomen sind multikatalytische Proteinasen, die (unter anderem) an zentralen Stellen des Zellzyklus Proteine, speziell auch die der Apoptoseinduktion, degradieren. Bislang konnte mit In-vitro-Untersuchungen die Wirksamkeit der Proteasomeninhibitoren bei der Apoptoseinduktion belegt werden, ebenso wie ihre zusätzliche Verstärkung zytotoxischer und antitumoraler Effekte. In vivo konnte bei Tieren und Patienten mit hormonrefraktären Prostatakarzinomen eine Reduktion des Tumorvolumens und des prostataspezifischen Antigens (PSA) beobachtet werden. PS-341 (Bortezomib, Velcade®) ist dabei der erste Proteasomeninhibitor, der klinisch bei Tumoren angewendet und in Studien untersucht wurde. Die vorliegende Übersichtsarbeit möchte die Verbindung zwischen den intrazellulären Wirkungen der Proteasomeninhibitoren und der Apoptoseinduktion sowie den aktuellen Stand klinischer Untersuchungen darstellen und diskutieren. Auch eigene Ergebisse der Proteasomeninhibition bei individuellen Prostatakarzinom-Zelllinien werden vorgestellt. Insgesamt muss man davon ausgehen, dass Proteasomeninhibitoren einen neuen therapeutischen Zugang im „molekularen Targeting” des Prostatakarzinoms eröffnen könnten.

Abstract

New perspectives in prostate cancer genesis and putative clinical management have emerged in recent years [29] [35]. Apoptosis plays a major role in this environment. Proteasome inhibitors block the action of a multicatalytic proteinase complex involved in the degradation of intracellular proteins, particularly with regard to cell cycle regulation and apoptosis. Numerous in vitro studies have demonstrated the ability of these compounds to induce apoptosis and enhance the activity of conventional tumoricidal agents in many cancer cell types, including prostate cancer cells. They point out the use of these potent inhibitors as a new potential molecular approach to the therapeutic management of prostate cancer. Furthermore, the action of proteasome inhibitors has been tested in animal models and in patients with hormone refractory prostate cancer, resulting in both PSA and tumor volume decrease. PS-341 (bortezomib, Velcade^TM) is the first proteasome inhibitor with clinical application in cancer therapy that has been used in clinical trials to date. This report reviews the current status of those papers that have tried to analyze the connection between the proteasome pathway and apoptosis. We present our results of proteasome inhibition in individual prostate cancer cell lines. Proteasomal inhibition may offer a new therapeutic access in “molecular targeting” of prostate cancer.

Schlüsselwörter

Prostatakarzinom/medikamentöse Therapie - Apoptose/Therapie/Physiologie - Boronate/Pharmakologie - Proteasomeninhibitoren/Pharmakologie - klinische Studie - Multienzymkomplexe/Antagonisten und Inhibitoren

Key words

Prostate cancer/drug therapy - apoptosis/drug effects/physiology - boronic acids/pharmacology - protease inhibitors/pharmacology - clinical study on humans - multienzyme complexes/antagonists and inhibitors

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