Abstract
BackgroundDrug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin’s lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression.MethodsImmunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The in vitro and in vivo experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH.ResultsWe demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues.ConclusionsOur findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy.
Highlights
Rituximab is an anti-CD20 chimeric monoclonal antibody and represents a revolutionary advance in B-NHL (B cell nonHodgkin’s lymphoma) treatment in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)
CD59 but not CD46 or CD55 is overexpressed in a multiple rituximab-treated mouse model xenografted with follicular lymphoma (FL) cells isolated from a patient [18]
We have reported that the widely expressed transcription factor Sp1 is responsible for the constitutive expression of CD59, whereas NF-kB and CREB regulate the inducible expression of CD59 via connection of CBP/p300 [23]
Summary
Rituximab is an anti-CD20 chimeric monoclonal antibody and represents a revolutionary advance in B-NHL (B cell nonHodgkin’s lymphoma) treatment in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Analyses of FcgRIIIa polymorphisms have clearly demonstrated that these polymorphisms are critical determinants of natural killer cell function, thereby demonstrating the importance of ADCC activity in determining the clinical efficacy of rituximab [5]. Adjuvant agents that directly abrogate the functions of mCRPs, such as CD46, CD55 and CD59, sensitize B-NHL cells to CDC, amplifying the therapeutic capacity of rituximab [13–16]. In a clinical study of chronic lymphocytic leukemia (CLL), the expression of CD59 but not CD55 significantly increased in patients who failed to clear CLL cells from circulation after rituximab treatment [19]. Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin’s lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. Sp1 regulates constitutive CD59 expression, whereas NF-kB and CREB regulate inducible CD59 expression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
