The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy

Abstract

BackgroundAggressive B-cell non-Hodgkin’s lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed.MethodsWe investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo.ResultsCBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro.ConclusionsCBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL.3a3Ge1vW8eA3YTTebu-sV5Video