Krebswissenschaft und -therapie

Ritonavir Exhibits Limited Efficacy as a Single Agent in Treating Aggressive Mantle Cell Lymphoma

Abstract

Tara M. Nordgren, Ganapati V. Hegde and Shantaram S. Joshi

Background: Mantle Cell Lymphoma (MCL) is an aggressive B cell malignancy accounting for 6% of non- Hodgkin’s lymphoma cases in the US. While various therapies are available to treat MCL, patients relapse within 3 to 4 years following treatment from therapy-resistant MCL, making MCL carry one of the worst prognoses of all non- Hodgkin’s B cell lymphomas. A better understanding of the biological mechanisms of relapse and therapy-resistance in MCL is vital for developing mechanisms to target relapsing MCL, and providing better care for patients. Recent studies implicate the NFκB pathway and survivin in promotion of aggressive, therapy-resistant MCL. Therefore, we tested the efficacy of inhibiting this pathway in three MCL lines (GP, recently-developed GRL, and JVM2) using the protease inhibitor ritonavir (Abbott Laboratories), which has been shown to downregulate NFκB targets, including survivin, in other hematological malignancies.

Methods: MCL cells were incubated with ritonavir then assessed for changes in proliferation, apoptosis, and activation of NFκB transcriptional targets. In addition, in vivo studies were performed to assess ritonavir’s utility as a single agent in MCL treatment using an immune-deficient mouse model of human MCL.

Results: When MCL cell lines were incubated with ritonavir in vitro, they exhibited reduced proliferation, increased apoptosis, and downregulation of NFκB pathway targets. However, no effect was seen when testing ritonavir as a single agent in vivo. Although, treatment with ritonavir plus vincristine in vitro revealed significant reduction in the proliferation of MCL compared to either treatment alone.

Conclusions: These studies suggest ritonavir is not suitable as a single-agent therapy for MCL. However, studies combining ritonavir plus vincristine in vitro suggest ritonavir may be effective in multi-pronged treatment approaches for MCL. These findings necessitate further studies to determine ritonavir’s utility within a multi-pronged treatment approach for treating therapy-resistant MCL.