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PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.

ABSTRACT: Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French-American-British subtypes M4 and M5). A 3-fold improvement in survival rates is observed in the parthanatos-positive versus -negative patient groups (hazard ratio [HR] = 0.28-0.37, p = 0.002-0.046). Manipulation of PARP-1 activity in parthanatos-competent cells reveals higher drug sensitivity in cells that have basal PARP-1 levels as compared with those subjected to PARP-1 overexpression or suppression. The same trends are observed in RNA expression databases and support the conclusion that PARP-1 can have optimal levels for favorable chemotherapeutic responses.

SUBMITTER: Maru B

PROVIDER: S-EPMC10518631 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.

Maru Bruktawit B Messikommer Alessandra A Huang Linhui L Seipel Katja K Kovecses Olivia O Valk Peter J M PJM Theocharides Alexandre P A APA Mercier Francois E FE Pabst Thomas T McKeague Maureen M Luedtke Nathan W NW

Cell reports. Medicine 20230907 9

Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French- ...[more]

PMID: 37683650

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Project description:BackgroundExcessive light exposure is a detrimental environmental factor that plays a critical role in the pathogenesis of retinal degeneration. However, the mechanism of light-induced death of retina/photoreceptor cells remains unclear. The mammalian/mechanistic target of rapamycin (mTOR) and Poly (ADP-ribose) polymerase-1 (PARP-1) have become the primary targets for treating many neurodegenerative disorders. The aim of this study was to elucidate the mechanisms underlying light-induced photoreceptor cell death and whether the neuroprotective effects of mTOR and PARP-1 inhibition against death are mediated through apoptosis-inducing factor (AIF).MethodsPropidium iodide (PI)/Hoechst staining, lentiviral-mediated short hairpin RNA (shRNA), Western blot analysis, cellular fraction separation, plasmid transient transfection, laser confocal microscopy, a mice model, electroretinography (ERG), and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which rapamycin/3-Aminobenzamide (3AB) exert neuroprotective effects of mTOR/PARP-1 inhibition in light-injured retinas.ResultsA parthanatos-like death mechanism was evaluated in light-injured 661 W cells that are an immortalized photoreceptor-like cell line that exhibit cellular and biochemical feature characteristics of cone photoreceptor cells. The death process featured over-activation of PARP-1 and AIF nuclear translocation. Either PARP-1 or AIF knockdown played a significantly protective role for light-damaged photoreceptors. More importantly, crosstalk was observed between mTOR and PARP-1 signaling and mTOR could have regulated parthanatos via the intermediate factor sirtuin 1 (SIRT1). The parthanatos-like injury was also verified in vivo, wherein either PARP-1 or mTOR inhibition provided significant neuroprotection against light-induced injury, which is evinced by both structural and functional retinal analysis. Overall, these results elucidate the mTOR-regulated parthanatos death mechanism in light-injured photoreceptors/retinas and may facilitate the development of novel neuroprotective therapies for retinal degeneration diseases.ConclusionsOur results demonstrate that inhibition of the mTOR/PARP-1 axis exerts protective effects on photoreceptors against visible-light-induced parthanatos. These protective effects are conducted by regulating the downstream factors of AIF, while mTOR possibly interacts with PARP-1 via SIRT1 to regulate parthanatos. Video Abstract Schematic diagram of mTOR interacting with PARP-1 to regulate visible light-induced parthanatos. Increased ROS caused by light exposure penetrates the nuclear membrane and causes nuclear DNA strand breaks. PARP-1 detects DNA breaks and synthesizes PAR polymers to initiate the DNA repair system that consumes a large amount of cellular NAD+. Over-production of PAR polymers prompts the release of AIF from the mitochondria and translocation to the nucleus, which leads to parthanatos. Activated mTOR may interact with PARP-1 via SIRT1 to regulate visible light-induced parthanatos.

Project description:This study aimed to investigate the changes in physical fitness and patient-reported outcomes as well as the correlation between these two factors in adult patients with newly diagnosed acute leukemia during chemotherapy. This was a longitudinal observational study. Patients were recruited from a tertiary hospital in China with a follow-up period of less than 90 days. Physical fitness was assessed using body mass index (BMI), mean skinfold thickness, waist-to-hip ratio, spirometry, mean grip strength, and flexibility at T1 (before chemotherapy), T2 (7-14 days after initial chemotherapy), and T3 (completely relieved or after two chemotherapy courses). A repeated-measures analysis of variance was used to analyze the physical fitness changes during follow-up. Multiple linear regression was used to analyze the factors influencing patient-reported outcomes. The study analyzed 121 patients. Changes in physical fitness during chemotherapy, including BMI, mean skinfold thickness, lung capacity and flexibility were not all equal at all three time points (F = 38.477, P < 0.001; F = 44.506, P < 0.001; F = 70.948, P < 0.001; and F = 70.965, P < 0.001), and post-hoc tests showed that they all trended to be decreasing before they were elevated (T2 < T3 < T1). The waist-to-hip ratio decreased and then increased (F = 12.138, P < 0.001,T2 < T3 = T1) and the mean grip strength remained stable (F = 0.137, P = 0.718). The total patient-reported outcome scale score decreased and subsequently increased (F = 362.507, P < 0.001,T2 < T1 < T3). BMI, mean skinfold thickness, spirometry, and flexibility influenced the patient-reported outcomes (B = 1.427,P < 0.001; B=-15.340,P < 0.001; B = 0.002,P = 0.014; B = 0.249,P < 0.001). Physical fitness affects patient-reported outcomes in those with acute leukemia. During chemotherapy, especially myelosuppression, healthcare providers should monitor patients' physical fitness and implement positive patient-appropriate interventions, such as exercise interventions, to promote better outcomes.

Project description:BACKGROUND: The molecular changes in vivo in acute myeloid leukemia cells early after start of conventional genotoxic chemotherapy are incompletely understood, and it is not known if early molecular modulations reflect clinical response. METHODS: The gene expression was examined by whole genome 44 k oligo microarrays and 12 k cDNA microarrays in peripheral blood leukocytes collected from seven leukemia patients before treatment, 2-4 h and 18-24 h after start of chemotherapy and validated by real-time quantitative PCR. Statistically significantly upregulated genes were classified using gene ontology (GO) terms. Parallel samples were examined by flow cytometry for apoptosis by annexin V-binding and the expression of selected proteins were confirmed by immunoblotting. RESULTS: Significant differential modulation of 151 genes were found at 4 h after start of induction therapy with cytarabine and anthracycline, including significant overexpression of 31 genes associated with p53 regulation. Within 4 h of chemotherapy the BCL2/BAX and BCL2/PUMA ratio were attenuated in proapoptotic direction. FLT3 mutations indicated that non-responders (5/7 patients, 8 versus 49 months survival) are characterized by a unique gene response profile before and at 4 h. At 18-24 h after chemotherapy, the gene expression of p53 target genes was attenuated, while genes involved in chemoresistance, cytarabine detoxification, chemokine networks and T cell receptor were prominent. No signs of apoptosis were observed in the collected cells, suggesting the treated patients as a physiological source of pre-apoptotic cells. CONCLUSION: Pre-apoptotic gene expression can be monitored within hours after start of chemotherapy in patients with acute myeloid leukemia, and may be useful in future determination of therapy responders. The low number of patients and the heterogeneity of acute myeloid leukemia limited the identification of gene expression predictive of therapy response. Therapy-induced gene expression reflects the complex biological processes involved in clinical cancer cell eradication and should be explored for future enhancement of therapy.

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PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.

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PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.

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