Small-molecule inhibitors targeting survival pathways in B-cell lymphoma

Currently, treatment of NHL is not curative in all patients. Conventional cytotoxic chemotherapeutic agents cause adverse side-effects to patients, while providing complete remission or partial remission with relapse following. The used of targeted therapy can circumvent these events while maintaining its anti-cancer efficacy.;The use of the small-molecule inhibitors (SMI) targeted to survival pathway known to be involved in the genesis or propagation of lymphoma was hypothesized to have an anti-lymphoma effect. Therefore, we used SMIs to the Bcl-2 and NF-kappaB pathways.;ApoG2 targets Bcl-2 family proteins (Bcl-2, Bcl-XL and Mcl-1) at the BH3 domain. ApoG2 inhibited the growth of WSU-FSCCL cells at an IC 50 of 109 nM, decreased the number of fresh lymphoma cells and activated the intrinsic apoptotic pathway. ApoG2 induced phenotypic apoptosis via AnnexinV/PI staing and caspase-9, 3 and 9 were activated and showed cleaved species. Additionally, proteins apoptotic pathway, PARP and AIF were also induced to their active form. In vivo, ApoG2 increase the life-span of lymphoma-bearing SCID mice.;MLN120B targets IKK via the ATP binding pocket. This prevents the phosphorylation of the NF-kappaB inhibitor IkappaBalpha. Downstream effectors of NF-kappaB can not be transcribed in this event. Therefore, inhibition of NF-kappaB with MLN120B is hypothesized to prevent cell cycle progression and induce apoptosis. MLN120B inhibits phosphorylation of IkappaBalpha in a concentration-dependent manner causing growth inhibition and increase in G0/G1 cells (WSU-FSCCL, WSU-DLCL 2 and WSU-WM). This inhibition was not robust enough to induce apoptosis indicating that MLN120B can be used as modulator to conventional chemotherapy. Therefore, MLN120B was used in conjunction with Cyclophosphamide monohydrate, Doxorubicin, or Vincristine. MLN120B had a synergist interaction with Vincristine inducing G2/M cell cycle arrest and apoptosis. MLN120B:Vincristine caused changes in protein levels of cell cycle and apoptotic regulators, confirming the arrested cell cycle and apoptotic phenotype. In vivo, MLN120B cause tumor delay of 10-11 days.;For the first time, these studies show that ApoG2 inhibition of the Bcl-2 family of proteins has anti-lymphoma properties and MLN120B inhibition of the NF-kappaB pathway synergistically potentiated the cytotoxicity of Vincristine. Taken together, targeting survival pathways are efficacious in the treatment of lymphoma.