Abstract 170: Thymoquinone-mediated suppression of NF- αB activity causes inhibition of cell viability and induces apoptosis in activated B-cell sub-type of diffuse large B-cell lymphoma

Abstract

Abstract Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoid malignancy and constitutes approximately 40% of all cases of non-Hodgkin's lymphoma (NHL). Despite improvement in treatment protocols, a large number of DLBCL cases remain refractory to treatment. DLBCL can be further classified as three distinct subtypes: germinal center B cell-like (GCB)-, activated B cell-like (ABC)-, and primary mediastinal B-cell lymphoma (PMBL). ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-kappa B (NF-κB) pathway. Yet the implication of NF-κB inhibition in ABC DLBCL need to be further elucidated. We have previously shown that Thymoquinone (TQ), a natural compound isolated from Nigella sativa, induces growth inhibition and induces apoptosis in several NHL cell lines. However its role in inhibition of growth and apoptosis has not been fully elucidated in ABC sub-type of DLBCL cell lines. We found that TQ treatment inhibits cell viability and induces apoptosis in a dose dependent manner in various ABC cell lines. Further more, we found that TQ treatment causes inactivation of IκBα and consequently inhibits NF-κB activity by decreasing the expression of p65 subunit of NF-κB in the nuclear compartment of ABC cell lines. In-activation of NF-κB survival pathway leads to induction of apoptosis via the mitochondrial apoptotic pathway initiated by conformational changes in the Bax protein leading to changes in the mitochondrial membrane potential and release of cytochrome c in the cytosole. Once cytochrome c is released, it leads to activation and cleavage of caspases-9 and -3 and cleavage of PARP. This leads to caspase dependent apoptosis in ABC cell lines. In addition, we also found that TQ treatment causes up-regulation of death receptor 5 (DR5), an important and essential receptor for tumor necrosis factor related apoptosis inducing ligand (TRAIL). However, up-regulation of DR5 does not play a role in TQ-induced apoptosis in ABC cell lines. Interestingly, combination of sub-toxic doses of TQ and TRAIL induces efficient significant apoptosis in ABC cell lines. These data show that TQ can be used alone or in combination with TRAIL to induce apoptosis in these aggressive sub-types of DLBCL and may play an important role in the management of DLBCL in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 170. doi:1538-7445.AM2012-170