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

Background Aggressive 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. Methods We 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. Results CBL0137, 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. Conclusions CBL0137 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.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells

“…In addition, the activated JNK signaling pathway is a key link in the apoptosis of intrahepatic cholangiocarcinoma cells by MLN2238 [ 102 ]. Furthermore, the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways are the mechanisms by which CBL0137 promotes ROS generation and induces the apoptosis and autophagy of aggressive B-cell non-Hodgkin’s lymphoma cells [ 103 ]. Therefore, the occurrence of cancer cell apoptosis largely depends on the JNK signaling pathway.…”

Comprehensive scientometrics and visualization study profiles lymphoma metabolism and identifies its significant research signatures

“…The PI3K/AKT/mTOR pathway is one of the most important intracellular signalling pathways, responsible for regulating biological processes such as cancer cell growth, proliferation and migration, which is closely related to cancer initiation and development and has become one of the popular pathways for researchers to develop cancer targeted drugs ( 68 – 70 ). Bcl2 is a star protein that inhibits apoptosis, and targeting the PI3K/AKT/mTOR pathway causes downregulation of Bcl2 protein expression, ultimately leading to lymphoma cell death ( 71 – 75 ). Furthermore, in clinical practice, helicobacter pylori is indeed a relatively marginal factor in all lymphoma subtypes and only associates with gastric mucosa-associated lymphoid tissue lymphoma ( 76 , 77 ).…”

“…(68)(69)(70). Bcl2 is a star protein that inhibits apoptosis, and targeting the PI3K/AKT/mTOR pathway causes downregulation of Bcl2 protein expression, ultimately leading to lymphoma cell death (71)(72)(73)(74)(75). Furthermore, in clinical practice, helicobacter pylori is indeed a relatively marginal factor in all lymphoma subtypes and only associates with gastric mucosa-associated lymphoid tissue lymphoma (76,77).…”