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Abstract
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.
Highlights
Targeting malignant B cells using rituximab has improved the efficacy of chemotherapy regimens used to treat patients with non-Hodgkin’s lymphoma
We have previously shown that repeated exposure of B-cell lymphoma cell lines Raji, RL, and SUDHL-4 to rituximab induced a rituximab-resistant phenotype
Parental SUDHL-4 cells were markedly resistant to chemotherapy when compared with Raji or RL, making fair comparison of chemotherapy sensitivity between rituximab-resistant cell lines (RRCL) derived from SUDHL-4 and Raji or RL impossible
Summary
Targeting malignant B cells using rituximab (anti-CD20) has improved the efficacy of chemotherapy regimens used to treat patients with non-Hodgkin’s lymphoma. We report that three rituximab-resistant cell lines (RRCL) derived from two distinct rituximab-sensitive cell lines (RSCL), Raji and RL, are markedly resistant to a panel of chemotherapeutic agents and to direct killing by rituximab due to a block in the initiation of apoptosis This apoptotic block seems to be the result of decreased expression of Bax and Bak in each RRCL. RRCLs that survived forced expression of Bak were resensitized to chemotherapy-induced apoptosis These data indicate that repeated exposure of malignant B cells to rituximab resulted in reduced expression of Bax and Bak, which contributes to their rituximab/chemotherapy-resistant phenotype by blocking initiation of apoptosis
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