Orelabrutinib and venetoclax synergistically induce cell death in double-hit lymphoma by interfering with the crosstalk between the PI3K/AKT and p38/MAPK signaling

Pan, Guangchao; Zhong, Min; Jian, Yao; Tan, Jinshui; Zheng, Huijian; Jiang, Yuelong; Tang, Yuan; Zhou, Hui; Qin, Dongmei; Yu, Xingxing; Liu, Long; Li, Zhifeng; Lin, Zhijuan; Jiang, Yunxia; Xu, Bing; Zha, Jun

doi:10.1007/s00432-022-04473-5

Cited by 4 publications

(5 citation statements)

References 38 publications

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“…The PI3K‐AKT‐mTOR and MAPK pathways play vital roles in cell motility 39,40 . Many studies showed that the PI3K‐AKT‐mTOR and MAPK pathways might crosstalk at various stages of signal transduction 41–44 . Surprisingly, our study showed that the PI3K‐AKT‐mTOR pathway regulated ACD without influencing apoptosis and that the MAPK pathway was involved in apoptosis without impacting ACD in ATG9b‐overexpressing HSCs.…”

Section: Discussioncontrasting

confidence: 56%

“… 39 , 40 Many studies showed that the PI3K‐AKT‐mTOR and MAPK pathways might crosstalk at various stages of signal transduction. 41 , 42 , 43 , 44 Surprisingly, our study showed that the PI3K‐AKT‐mTOR pathway regulated ACD without influencing apoptosis and that the MAPK pathway was involved in apoptosis without impacting ACD in ATG9b‐overexpressing HSCs. The results indicate that a change in the PI3K‐AKT‐mTOR pathway via activators affects apoptosis to a lesser extent than ATG9b overexpression and that the change in the MAPK pathway via inhibitors affects ACD to a lesser degree than ATG9b overexpression.…”

Section: Discussionmentioning

confidence: 65%

“…39,40 Many studies showed that the PI3K-AKT-mTOR and MAPK pathways might crosstalk at various stages of signal transduction. [41][42][43][44] Surprisingly, our study showed that the PI3K-AKT-mTOR pathway regulated ACD without influencing apoptosis and that the MAPK…”

Section: Discussionmentioning

confidence: 65%

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Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Wang,

Ding,

Xiu

et al. 2023

J Cellular Molecular Medi

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Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy‐related protein 9b (ATG9b) in HSC ACD was detected using co‐immunoprecipitation and co‐localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol‐treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5‐ATG12‐LC3 compartments and increased the co‐localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b‐induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 65%

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Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Wang,

Ding,

Xiu

et al. 2023

J Cellular Molecular Medi

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“…Aberrant activation of the PI3K/AKT/mTOR pathway has been observed in critical subgroups of DLBCL samples, driven by chronic BCR signaling activation or loss of expression of phosphatases and PTEN (Xu et al 2023 ). The combination of orelabrutinib and venetoclax synergistically induces DHL cell death by modulating the PI3K/AKT and P38/MAPK pathways, inhibiting cell proliferation, and inducing cell cycle arrest (Pan et al 2023 ). Our sequencing results highlight the PI3K/AKT and mTOR signaling pathways as potential targets in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

“…The combination of orelabrutinib and rituximab could preserve rituximab-induced NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhance tumor cell apoptosis in vitro (Yu et al 2021 ). Orelabrutinib combined with venetoclax synergistically could induce DHL cell death and cell cycle arrest, as well as inhibit cell proliferation (Pan et al 2023 ). A once-daily orelabrutinib dosing regimen achieves sustained BTK occupancy at 24 h (Dhillon 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Chidamide and orelabrutinib synergistically induce cell cycle arrest and apoptosis in diffuse large B-cell lymphoma by regulating the PI3K/AKT/mTOR pathway

Wu,

Chen,

et al. 2024

J Cancer Res Clin Oncol

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Objective The initial therapeutic approach for diffuse large B-cell lymphoma (DLBCL) entails a rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. However, 40% of patients exhibit suboptimal responses, with some experiencing relapse and refractory conditions. This study aimed to explore novel therapeutic strategies and elucidate their underlying mechanisms in DLBCL. Methods Bioinformatics techniques were employed to scrutinize correlations between the HDAC1, HDAC2, HDAC3, HDAC10, BTK, MYC, TP53, and BCL2 genes in DLBCL. In vitro experiments were conducted using DB and SU-DHL-4 cells treated with chidamide, orelabrutinib, and a combination of both. Cell viability was assessed by cell counting kit-8. Cell apoptosis and the cell cycle were determined using flow cytometry. Reactive oxygen species (ROS) production and mitochondrial function were assessed through ROS and JC-1 staining. RNA sequencing and western blot analyses were conducted to elucidate the molecular mechanisms underlying the combined action of chidamide and orelabrutinib in DLBCL cells. Results This investigation revealed markedly enhanced antiproliferative effects when chidamide was combined with orelabrutinib. Compusyn software analysis indicated a synergistic effect of chidamide and orelabrutinib in inhibiting DLBCL cell proliferation, with a combination index (CI) < 1. This synergy further manifested as augmented cell cycle arrest, apoptosis induction, the downregulation of cell cycle-associated and antiapoptotic proteins, and the upregulation of proapoptotic proteins. Furthermore, the western blot and RNA-Seq findings suggested that combining chidamide and orelabrutinib modulated the PI3K/AKT/mTOR signaling pathway, thereby promoting DLBCL cell cycle arrest and apoptosis. Conclusion The findings of this study provide a compelling justification for the clinical utilization of chidamide and orelabrutinib to treat relapsed/refractory DLBCL.

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11,12-EET suppressed LPS induced TF expression and thrombus formation by accelerating mRNA degradation rate via strengthening PI3K-Akt signaling pathway and inhibiting p38-TTP pathway

Luo¹,

Yang²,

Fu³

et al. 2023

Prostaglandins & Other Lipid Mediators

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Orelabrutinib and venetoclax synergistically induce cell death in double-hit lymphoma by interfering with the crosstalk between the PI3K/AKT and p38/MAPK signaling

Cited by 4 publications

References 38 publications

Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis

Chidamide and orelabrutinib synergistically induce cell cycle arrest and apoptosis in diffuse large B-cell lymphoma by regulating the PI3K/AKT/mTOR pathway

11,12-EET suppressed LPS induced TF expression and thrombus formation by accelerating mRNA degradation rate via strengthening PI3K-Akt signaling pathway and inhibiting p38-TTP pathway

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