BCL2 inhibitor

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS)...

BACKGROUND: Patients with acute myeloid leukaemia have high rates of relapse, especially if they are unable to complete standard consolidation strategies or allogeneic haematopoietic stem-cell transplantation (HSCT). The phase 3 QUAZAR AML-001 study showed an overall survival benefit with oral azacitidine maintenance. The BCL2 inhibitor venetoclax is highly active in acute myeloid leukaemia and synergistic with azacitidine. We aimed to evaluate the efficacy and safety of low dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia...

Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines...

Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need...

BH3 mimetics, including the BCL2/BCLXL /BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...

Therapeutic targeting of apoptosis with small molecule B-cell lymphoma 2 (BCL-2) inhibition with venetoclax is highly efficacious in CLL, leading to sustained deep responses, particularly among patients with treatment-naïve disease with favorable prognostic markers. Patients with unfavorable genetic characteristics such as TP53 aberration and unmutated IGHV may also derive durable benefits, but their remission duration after time-limited venetoclax-containing combination therapy is shorter, particularly in patients with relapsed/refractory disease...

Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), R-CHOP (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21)...

Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). While inhibitors targeting these pathways effectively suppress the diseases, they fall short in providing enduring remission, largely attributed to cytostatic nature of these drugs. Even combinations of these drugs are ineffective in achieving sustained remission. Enhanced MAPK signaling besides promoting proliferation and survival triggers a pro-apoptotic response...

BACKGROUND: miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined. METHODS: To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter...

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. CLL is a highly heterogeneous disease: some patients may never require therapy and others relapse several times after different therapeutic strategies. Therefore, in CLL, prognostic markers are essential to capture high-risk patients for different clinical endpoints including early treatment requirement, early progression after BTK or BCL2 inhibitors and Richter transformation. In early stage CLL, different biological and clinical biomarkers have been identified to predict time to treatment requirement that could be used to identify the most appropriate population for early intervention clinical trial...

BACKGROUND: Anaplastic Thyroid Carcinoma (ATC) is a rare and deadly malignant tumor in humans. It is prone to developing resistance to radiotherapy and chemotherapy. Molecular targeted therapy offers a novel way to treat ATC. The BRAF mutation is closely associated with many cancers, including thyroid carcinoma. Vemurafenib, a small-molecule inhibitor, is specifically designed to target the mutant serine/threonine kinase BRAF. The objective of this study is to elucidate the regulatory mechanisms underlying the effects of vemurafenib on human anaplastic thyroid carcinoma cell line FRO and to assess its potential therapeutic role...

The activated B cell (ABC) subset of diffuse large B cell lymphoma (DLBCL) is characterized by chronic B cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small molecule inhibitor, ABBV-MALT1, that potently shuts down B cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition...

Esculeoside A (ESA) is a tomato-derived glycoside with antioxidant and anti-inflammatory properties. The protective effect of ESA against diabetic retinopathy is not well-investigated and was the core objective of this study. In addition, we tested if such protection involves the activation of Nrf2 signaling. Type 1 diabetes mellitus (T1DM) was induced in adult Wistar male rats by an intraperitoneal injection of streptozotocin (65 mg/kg). Non-diabetic and T1DM rats were divided into two subgroup groups given either the vehicle or ESA (100 mg)/kg...

BACKGROUND: Long non-coding RNAs (lncRNAs) can be severed as competing endogenous RNAs (ceRNAs) to regulate target genes or mRNAs via sponging microRNAs (miRNAs). This study explored the effect of LINC01554 on liver cancer cells through the ceRNA mechanism. METHODS: Five significantly down-regulated lncRNAs were selected for further verification, and then through bioinformatics, interactive miRNAs and mRNAs of lncRNAs were identified. The relationship between LINC01554, miR-148b-3p and EIF4E3 was detected by the dual luciferase reporter gene assay...

BACKGROUND: This study seeks to investigate the impacts of Lactobacillus reuteri (L. reuteri) on hepatic ischemia-reperfusion (I/R) injury and uncover the mechanisms involved. METHODS: Mice in the I/R groups were orally administered low and high doses of L.reuteri (L.reuteri-low and L. reuteri-hi; 1 × 1010 CFU/d and 1 × 1011 CFU/d), for 4 weeks prior to surgery. Following this, mice in the model group were treated with an Nrf2 inhibitor (ML-385), palmitoylcarnitine, or a combination of both...

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BACKGROUND AND AIMS: Acute kidney injury (AKI) due to renal ischemia-reperfusion injury (RIRI) is associated with high morbidity and mortality, with no renoprotective drug available. Previous research focused on single drug targets, yet this approach has not reached translational success. Given the complexity of this condition, we aimed to identify a disease module and apply a multitarget network pharmacology approach. METHODS: Identification of a disease module with potential drug targets was performed utilizing Disease Module Detection algorithm using NADPH oxidases (NOXs) as seeds...

ABT737 is used as a specific BCL2 inhibitor, which can treat papillary thyroid carcinoma (PTC). However, the effect of ABT737 on PTC cell apoptosis is limited. Moreover, BCL2 inhibition causes the activation of Beclin1-dependent autophagy. Our study aimed to explore the effects of autophagy and Beclin1 on ABT737 efficacy in PTC. The experimental data showed that ABT737 synchronously enhanced autophagic activity and apoptosis level in PTC cells. ABT737 also promoted the dissociation of BCL2-Beclin1 and BCL2-Bax complexes...

Doxorubicin (DOX), an anthracycline chemotherapy, plays a prominent role in the treatment of various cancers. Unfortunately, its nephrotoxic effects limit its dosing and expose cancer survivors to increased morbidity and mortality. This study examined the nephroprotective effects of eriodictyol, a natural polyphenolic flavanone, in DOX-treated rats and the molecular pathways involved. Forty adult rats were divided into five groups (8/group): Control; eriodictyol (20 mg/kg/day); DOX (2.5 mg/kg, twice/week); DOX + Eriodictyol; and DOX + Eriodictyol + Compound C (CC), an AMPK inhibitor (0...

Chemoresistance to cisplatin remains a significant challenge affecting the prognosis of advanced oral squamous cell carcinoma (OSCC). However, the specific biomarkers and underlying mechanisms responsible for cisplatin resistance remain elusive. Through comprehensive bioinformatic analyses, we identified a potential biomarker, BCL2 associated athanogene-1 (BAG1), showing elevated expression in head and neck squamous cell carcinoma (HNSCC). Since OSCC represents the primary pathological type of HNSCC, we investigated BAG1 expression in human tumor tissues and cisplatin resistant OSCC cell lines, revealing that silencing BAG1 induced apoptosis in cisplatin-resistant cells both in vitro and in vivo...