RESUMO
Primary effusion lymphoma (PEL) is defined as a rare subtype of nonHodgkin's B cell lymphoma, which is caused by Kaposi's sarcomaassociated 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 antitumor compounds against PEL, the authors previously developed a pyrrolidiniumtype fullerene derivative, 1,1,1',1'tetramethyl [60]fullerenodipyrrolidinium diiodide (derivative #1), which induced the apoptosis of PEL cells via caspase9 activation. In the present study, the growth inhibitory effects of pyrrolidiniumtype (derivatives #1 and #2), pyridiniumtype (derivatives #3 and #5 to #9) and aniliniumtype fullerene derivatives (derivative #4) against PEL cells were evaluated. This analysis revealed a pyridiniumtype derivative (derivative #5; 3â5'(etho xycarbonyl)1',5'dihydro2'H[5,6]fullerenoC60Ih[1,9c]pyrrol2'yl]1methylpyridinium iodide), which exhibited antitumor activity against PEL cells via the downregulation of Wnt/ßcatenin signaling. Derivative #5 suppressed the viability of KSHVinfected PEL cells compared with KSHVuninfected Blymphoma cells. Furthermore, derivative #5 induced the destabilization of ßcatenin and suppressed ßcateninTCF4 transcriptional activity in PEL cells. It is known that the constitutive activation of Wnt/ßcatenin signaling is essential for the growth of KSHVinfected cells. The Wnt/ßcatenin activation in KSHVinfected cells is mediated by KSHV latencyassociated nuclear antigen (LANA). The data demonstrated that derivative #5 increased ßcatenin phosphorylation, which resulted in ßcatenin polyubiquitination and subsequent degradation. Thus, derivative #5 overcame LANAmediated ßcatenin 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 pyridiniumtype 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.
Assuntos
Antineoplásicos/farmacologia , Fulerenos/farmacologia , Herpesvirus Humano 8/efeitos dos fármacos , Linfoma de Efusão Primária/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Camundongos , Compostos de Piridínio/farmacologiaRESUMO
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 lymphoma and is frequently resistant to conventional chemotherapies. Therefore, it is critical to investigate novel therapeutic options for PEL. Capsaicin is a pungent component of chili pepper and possesses unique pharmacological effects, such as pain relief, anti-microbial and anti-cancer properties. Here, we demonstrate that capsaicin markedly inhibited the growth of KSHV latently infected PEL cells by inhibiting ERK, p38 MAPK and expression hIL-6, which are known to contribute to PEL growth and survival. The underlying mechanism of action by capsaicin was through the inhibition of ERK and p38 MAPK phosphorylation and signaling that affected hIL-6 expression. As a result, capsaicin induced apoptosis in PEL cells in a caspase-9 dependent manner. In line with these results, ERK (U0126) and p38 MAPK (SB203580) specific signaling inhibitors suppressed hIL-6 expression and attenuated cell growth in PEL cells. Furthermore, the addition of hIL-6 neutralizing antibody to culture medium suppressed the growth of PEL cells. We also demonstrate that capsaicin suppressed PEL cell growth in the absence of nascent viral replication. Finally, we confirmed ex vivo treatment of capsaicin attenuated PEL development in SCID mice. Taken together, capsaicin could represent a lead compound for PEL therapy without the risk of de novo KSHV infection.