Panicker, N. | Search bioRxiv

bioRxiv2026

(E,E)-bisantrene suppresses MYC expression and displays anti-leukemic activity in acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is genetically diverse with a high unmet clinical need for improved treatment options. Dysregulation of the transcription factor MYC plays a central role in AML progression and therapeutic resistance. (E,E)-bisantrene was recently found to inhibit MYC transcription and downstream activity via G-quadruplex DNA stabilization. This study aimed to evaluate the mechanism of action and preclinical activity of (E,E)-bisantrene in AML. Methods: The in vitro and in vivo activity of (E,E)-bisantrene was determined in a variety of AML models (cell lines, xenograft mouse models, and ex vivo human AML mononuclear cells). Transcriptomic, proteomic and phosphoproteomic analyses were performed after treatment with (E,E)-bisantrene. Analyses of -omics data to identify enriched pathways and upstream regulators were performed. Results: (E,E)-bisantrene demonstrated potent anti-proliferative activity across a panel of AML cell lines, inducing apoptosis and reducing S phase proportions. (E,E)-bisantrene significantly prolonged survival in cell- and patient-derived xenograft models of AML. Mechanistically, RNA-seq and proteomic analysis of MOLM13 and MV4-11 cells treated with (E,E)-bisantrene showed significant reductions in the activity of MYC and E2F, together with the cell cycle regulators CDK1/2/4/5. Transcript and protein levels of MYC were reduced in a dose- and time-dependent manner. TP53 and inflammation-associated transcript signatures were also observed. Conclusion: Anti-proliferative activity of (E,E)-bisantrene in preclinical AML models was associated with a downregulation of MYC, CDK1/2/4/5 and E2F. This study supports the ongoing clinical evaluation of (E,E)-bisantrene in AML where MYC is a clinically relevant driver of disease aggressiveness and therapy resistance.

cancer biology↗

bioRxiv2025

Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimers disease (AD), yet its role in amyloid-{beta} (A{beta}) pathology remains unclear. Here, we show that PARP1 activation drives A{beta} pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric A{beta}1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein (APP) and BACE1 levels, altered {gamma}-secretase complex composition, and enhanced A{beta} degradation via neprilysin. These findings position PARP1 as a critical mediator of A{beta} toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD. Significance StatementOur study identifies poly(ADP-ribose) (PAR) as an elevated biomarker in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimers disease, correlating with established markers of amyloid pathology. We demonstrate that PARP1, the enzyme responsible for PAR synthesis, is activated by neurotoxic A{beta}1-42 and mediates neuronal death, amyloid plaque formation, neuroinflammation, and cognitive deficits in a mouse model of AD. Importantly, genetic ablation of PARP1 not only protects neurons from A{beta} toxicity but also reduces amyloid burden by suppressing A{beta} production and enhancing its degradation. These findings highlight PARP1 as a critical regulator of amyloid pathology and neurodegeneration, and suggest that PARP1 inhibition may offer a promising therapeutic avenue for Alzheimers disease by simultaneously targeting multiple pathogenic mechanisms.

neuroscience↗