Distinct cellular and therapeutic effects of obatoclax in rituximab‐sensitive and ‐resistant lymphomas

Abstract

Bcl-2 proteins represent a rheostat that controls cellular viability. Obatoclax, a BH3-mimetic, has been designed to specifically target and counteract anti-apoptotic Bcl-2 proteins. We evaluated the biological effects of obatoclax on the anti-tumour activity of rituximab and chemotherapy agents. Obatoclax induced cell death of rituximab/chemotherapy-sensitive (RSCL), -resistant cell lines (RRCL) and primary tumour-cells derived from patients with B-cell lymphomas (N=39). Obatoclax also enhanced the activity of rituximab and had synergistic activity when combined with chemotherapy agents. The ability of Obatoclax to induce PARP cleavage varied between patient samples and was not observed in some RRCL. Inhibition of caspase activity did not affect obatoclax activity, suggesting the existence of caspase-independent death pathways. Autophagy was detected by LC3 conversion and/or electron microscopy in RRCL and in patient-derived tumour cells. Moreover, obatoclax activity was inhibited by Beclin-1 knockdown. In summary, obatoclax is an active Bcl-2 inhibitor that potentiates the activity of chemotherapy agents and, to a lesser degree, rituximab. Defining the molecular events triggered by obatoclax is necessary to further its clinical development and identify potential biomarkers that are predictive of response.

Prolyl Hydroxylase 3 Attenuates MCL-1–Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells

“…The efficacy of GX15-070 in reducing the ATP production of PHD3-underexpressing cells might however be explained by the fact that GX15-070 treatment downregulates the overall abundance of MCL-1 protein (41). Obviously, we do not want to rule out that GX15-070 affects ATP production in PHD3-underexpressing cells via mechanisms distinct from the effects of mitochondrial MCL-1 (42,43). Taken together, our analyses identified MCL-1 as a novel molecular player, regulating tumor cell metabolism and invasion downstream PHD3.…”

Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

“…21,22 Neoplastic B cells were isolated from pretreatment biopsy tissue obtained from patients with B-cell non-Hodgkin lymphoma or lymphocyte-predominant Hodgkin lymphoma receiving therapy at Roswell Park Cancer Institute (RPCI) as previously described. 23 …”

Epstein-Barr Virus Infection and Altered Control of Apoptotic Pathways in Posttransplant Lymphoproliferative Disorders

“…Notably, it was shown that Bcl-2 antisense enhances the in vitro and in vivo response of EBV-associated lymphoproliferative diseases to the anti-CD 20 antibody rituximab [33], a treatment which is frequently considered in PTLD patients and has been shown to be effective in other B cell malignancies (reviewed by Masood et al [34]). Recent studies on new generation molecules with anti-Bcl-2 reactivity report on their potentiating role of chemotherapeutic activity, as well as on anti-CD 20 antibody, making this easily applicable molecule an ideal predictive marker [35]. …”