A pyridinium‑type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β‑catenin.

Abstract

Primary effusion lymphoma (PEL) is defined as a rare subtype of non-Hodgkin's B cell lymphoma, which is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive type of lymphoma and is frequently resistant to conventional chemotherapeutics. Therefore, the discovery of novel drug candidates for the treatment of PEL is of utmost importance. In order to discover potential novel anti-tumor compounds against PEL, the authors previously developed a pyrrolidinium-type fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide (derivative #1), which induced the apoptosis of PEL cells via caspase-9 activation. In the present study, the growth inhibitory effects of pyrrolidinium-type (derivatives #1 and #2), pyridinium-type (derivatives #3 and #5 to #9) and anilinium-type fullerene derivatives (derivative #4) against PEL cells were evaluated. This analysis revealed a pyridinium-type derivative (derivative #5; 3- 5′-(etho-xycarbonyl)-1′,5′-dihydro-2′H-[5,6]fullereno-C60-Ih-[1,9-c]pyrrol-2′-yl]-1-methylpyridinium iodide), which exhibited antitumor activity against PEL cells via the downregulation of Wnt/β-catenin signaling. Derivative #5 suppressed the viability of KSHV-infected PEL cells compared with KSHV-uninfected B-lymphoma cells. Furthermore, derivative #5 induced the destabilization of β-catenin and suppressed β-catenin-TCF4 transcriptional activity in PEL cells. It is known that the constitutive activation of Wnt/β-catenin signaling is essential for the growth of KSHV-infected cells. The Wnt/β-catenin activation in KSHV-infected cells is mediated by KSHV latency-associated nuclear antigen (LANA). The data demonstrated that derivative #5 increased β-catenin phosphorylation, which resulted in β-catenin polyubiquitination and subsequent degradation. Thus, derivative #5 overcame LANA-mediated β-catenin stabilization. Furthermore, the administration of derivative #5 suppressed the development of PEL cells in the ascites of SCID mice with tumor xenografts derived from PEL cells. On the whole, these findings provide evidence that the pyridinium-type fullerene derivative #5 exhibits antitumor activity against PEL cells in vitro and in vivo. Thus, derivative #5 may be utilized as a novel therapeutic agent for the treatment of PEL.