Abstract：
Rituximab (RTX) resistance is a notable challenge in treating diffuse large B-cell lymphoma (DLBCL). β-Sitosterol (β-ST) is a plant sterol that has been found in a broad variety of fruits, spices, and medicinal plants. The antineoplastic properties of β-ST are established in various solid malignancies; however, its effect on DLBCL is uncharted. This study investigates the role of β-ST in DLBCL as well as the underlying mechanisms. Our findings indicated that β-ST impeded DLBCL cell proliferation in a concentration- and time-dependent manner. β-ST appeared to alter sphingolipid metabolism, facilitate acid sphingomyelinase (ASM) translocation to the plasma membrane, augment ceramide platforms through increased ceramide synthesis, and consequently induce apoptosis in DLBCL cells. Furthermore, we found that RTX initiated both apoptotic and survival pathways in vitro, with the former contingent on the transient activation of the ASM, and β-ST could amplify the anti-DLBCL efficacy of RTX by modulating ASM/Ceramide (Cer) signaling. Collectively, our findings elucidate the mechanistic role of β-ST in DLBCL and underscore its potential in amplifying the antineoplastic efficacy of RTX via ASM activation, proposing a potential avenue to improve the efficacy of RTX therapy.
摘要：
利妥昔单抗（RTX）耐药性是治疗弥漫性大B细胞淋巴瘤（DLBCL）的显着挑战。β-谷甾醇（β-ST）是一种植物甾醇，已在各种水果中发现，香料,和药用植物。β-ST的抗肿瘤特性已在各种实体恶性肿瘤中确立；然而，它对DLBCL的影响是未知的。本研究探讨了β-ST在DLBCL中的作用及其机制。我们的发现表明，β-ST以浓度和时间依赖性方式阻碍了DLBCL细胞的增殖。β-ST似乎改变了鞘脂代谢，促进酸性鞘磷脂酶（ASM）易位到质膜，通过增加神经酰胺合成来增强神经酰胺平台，并因此诱导DLBCL细胞凋亡。此外，我们发现RTX在体外启动了凋亡和存活途径，前者取决于ASM的瞬时激活，β-ST可以通过调节ASM/神经酰胺（Cer）信号增强RTX的抗DLBCL功效。总的来说，我们的发现阐明了β-ST在DLBCL中的机制作用，并强调了其通过ASM激活增强RTX抗肿瘤功效的潜力，提出了提高RTX治疗疗效的潜在途径。
