Olejniczak Scott H, Hernandez-Ilizaliturri Francisco J, Clements James L, Czuczman Myron S
Departments of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Clin Cancer Res. 2008 Mar 1;14(5):1550-60. doi: 10.1158/1078-0432.CCR-07-1255.
Targeting malignant B cells using rituximab (anti-CD20) has improved the efficacy of chemotherapy regimens used to treat patients with non-Hodgkin's lymphoma. Despite the promising clinical results obtained using rituximab, many patients relapse with therapy-resistant disease following rituximab-based treatments. We have created a cell line model of rituximab resistance using three B-cell non-Hodgkin's lymphoma-derived cell lines (Raji, RL, and SUDHL-4). In an attempt to define strategies to overcome rituximab resistance, we sought to determine the chemotherapy sensitivity of our rituximab-resistant cell lines (RRCL).
Parental, rituximab-sensitive cell lines (RSCL) Raji, RL, and SUDHL-4, along with RRCLs derived from them, were exposed to several chemotherapeutic agents with different mechanisms of action and the ability of these agents to induce apoptotic cell death was measured. Expression of multidomain Bcl-2 family proteins was studied as potential mediators of chemotherapy/rituximab resistance.
We found that RRCLs are resistant to multiple chemotherapeutic agents and have significantly decreased expression of the Bcl-2 family proteins Bax, Bak, and Bcl-2. RRCLs do not undergo rituximab- or chemotherapy-induced apoptosis but die in a caspase-dependent manner when either wild-type Bax or Bak is exogenously expressed. Furthermore, forced expression of Bak sensitized RRCL to chemotherapy-induced apoptosis.
Whereas a single or limited exposure of lymphoma cells to rituximab may lead to a favorable ratio of proapoptotic to antiapoptotic Bcl-2 family proteins, repeated exposure to rituximab is associated with a therapy-resistant phenotype via modulation of Bax and Bak expression.
使用利妥昔单抗（抗CD20）靶向恶性B细胞已提高了用于治疗非霍奇金淋巴瘤患者的化疗方案的疗效。尽管使用利妥昔单抗取得了令人鼓舞的临床结果，但许多患者在接受基于利妥昔单抗的治疗后会出现治疗抵抗性疾病复发。我们使用三种B细胞非霍奇金淋巴瘤来源的细胞系（Raji、RL和SUDHL-4）创建了利妥昔单抗耐药细胞系模型。为了确定克服利妥昔单抗耐药性的策略，我们试图确定我们的利妥昔单抗耐药细胞系（RRCL）对化疗的敏感性。
将亲代、利妥昔单抗敏感细胞系（RSCL）Raji、RL和SUDHL-4以及由它们衍生的RRCL暴露于几种具有不同作用机制的化疗药物，并测量这些药物诱导凋亡性细胞死亡的能力。研究多结构域Bcl-2家族蛋白的表达作为化疗/利妥昔单抗耐药性的潜在介导因素。
我们发现RRCL对多种化疗药物耐药，并且Bcl-2家族蛋白Bax、Bak和Bcl-2的表达显著降低。RRCL不会发生利妥昔单抗或化疗诱导的凋亡，但当外源性表达野生型Bax或Bak时，会以半胱天冬酶依赖性方式死亡。此外，Bak的强制表达使RRCL对化疗诱导的凋亡敏感。
虽然淋巴瘤细胞单次或有限暴露于利妥昔单抗可能导致促凋亡与抗凋亡Bcl-2家族蛋白的有利比例，但反复暴露于利妥昔单抗会通过调节Bax和Bak的表达而与治疗抵抗性表型相关。
