Crosstalk between Noxa, Bcl-2, and ceramide in mediating p53-dependent apoptosis in Molt-4 human T-cell leukemia

Kobeissy, Hadile; Hage‐Sleiman, Rouba; Dakdouk, Zeinab; Kozhaya, Lina; Dbaibo, Ghassan

doi:10.1007/s11010-020-03874-9

Cited by 11 publications

(5 citation statements)

References 40 publications

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“…Pmaip1 is a pro-apoptotic Bcl-2 homology domain 3-only protein [ 31 ]. It has been demonstrated that the Pmaip1-mediated pathway plays an important part in IR-induced apoptotic response [ 41 , 42 , 43 ]. Pmaip1 knockout mice showed resistance to IR-induced intestinal crypt cell apoptosis and survived longer than WT mice [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis

Lin

Luo

et al. 2021

Nutrients

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It is urgent to seek new potential targets for the prevention or relief of gastrointestinal syndrome in clinical radiation therapy for cancers. Vitamin D, mediated through the vitamin D receptor (VDR), has been identified as a protective nutrient against ionizing radiation (IR)-induced damage. This study investigated whether VDR could inhibit IR-induced intestinal injury and explored underlying mechanism. We first found that vitamin D induced VDR expression and inhibited IR-induced DNA damage and apoptosis in vitro. VDR was highly expressed in intestinal crypts and was critical for crypt stem/progenitor cell proliferation under physiological conditions. Next, VDR-deficient mice exposed to IR significantly increased DNA damage and crypt stem/progenitor cell apoptosis, leading to impaired intestinal regeneration as well as shorter survival time. Furthermore, VDR deficiency activated the Pmaip1-mediated apoptotic pathway of intestinal crypt stem/progenitor cells in IR-treated mice, whereas inhibition of Pmaip1 expression by siRNA transfection protected against IR-induced cell apoptosis. Therefore, VDR protects against IR-induced intestinal injury through inhibition of crypt stem/progenitor cell apoptosis via the Pmaip1-mediated pathway. Our results reveal the importance of VDR level in clinical radiation therapy, and targeting VDR may be a useful strategy for treatment of gastrointestinal syndrome.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis

Lin

Luo

et al. 2021

Nutrients

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“…These were selected for evaluation due to their different degree of drug target expression, specifically Bruton’s tyrosine kinase (BTK) and B-cell lymphoma 2 (Bcl-2). HL-60 cells express both BTK [ 16 ] and Bcl-2 [ 17 ], while K-562 [ 18 , 19 ] cells only express BTK and MOLT-4 [ 20 , 21 ] cells express only Bcl-2.…”

Section: Methodsmentioning

confidence: 99%

Design and Characterization of a Novel Venetoclax-Zanubrutinib Nano-Combination for Enhancing Leukemic Cell Uptake and Long-Acting Plasma Exposure

Griffin

et al. 2023

Pharmaceutics

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Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved safety and tolerability compared to conventional, nontargeted chemotherapies. However, dosing with a single agent frequently leads to drug resistance; asynchronous coverage due to the peak-and-trough time-course of two or more oral drugs has prevented drug combinations from simultaneously knocking out the respective drugs’ targets for sustained leukemia suppression. Higher doses of the drugs may potentially overcome asynchronous drug exposure in leukemic cells by saturating target occupancy, but higher doses often cause dose-limiting toxicities. To synchronize multiple drug target knockout, we have developed and characterized a drug combination nanoparticle (DcNP), which enables the transformation of two short-acting, orally active leukemic drugs, venetoclax and zanubrutinib, into long-acting nanoformulations (VZ-DCNPs). VZ-DCNPs exhibit synchronized and enhanced cell uptake and plasma exposure of both venetoclax and zanubrutinib. Both drugs are stabilized by lipid excipients to produce the VZ-DcNP nanoparticulate (d ~ 40 nm) product in suspension. The VZ-DcNP formulation has enhanced uptake of the two drugs (VZ) in immortalized leukemic cells (HL-60), threefold over that of its free drug counterpart. Additionally, drug-target selectivity of VZ was noted with MOLT-4 and K562 cells that overexpress each target. When given subcutaneously to mice, the half-lives of venetoclax and zanubrutinib were extended by approximately 43- and 5-fold, respectively, compared to an equivalent free VZ. Collectively, these data suggest that VZ in VZ-DcNP warrant consideration for preclinical and clinical development as a synchronized and long-acting drug-combination for the treatment of leukemia.

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“…Stepwise, bimodal activation of BAX-BAK is directly induced by BID, BIM, PUMA, and NOXA [26]. It has been demonstrated that p53 can transcriptionally activate pro-apoptotic BCL-2 Homology domain-3 (BH3)-only genes, including p53 upregulated modulator of apoptosis (PUMA) and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1 or NOXA) [163].…”

Section: Puma and Noxamentioning

confidence: 99%

Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context

Saddam,

Paul,

Habib

et al. 2024

Egypt J Med Hum Genet

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Apoptosis, also known as the programmed death of cells, is responsible for maintaining the homeostasis of tissues, and this function is carried out by caspases. The process of apoptosis is carried out via two distinct pathways: the extrinsic pathway, which is governed by death receptors, and the intrinsic pathway, also known as the mitochondrial pathway. The BCL-2 protein family encoded by the BCL-2 gene, located at the 18q21.33 chromosomal location, is in charge of regulating the intrinsic pathway, which is responsible for inducing cell death via the permeabilization of the mitochondrial membrane and the release of apoptosis-inducing components. The BCL-2 homology (BH1, BH2, BH3, BH4) domains of this family proteins are crucial for their functioning, and their common BH domains allow interactions between members of the same family and can also serve as indications of pro- or anti-apoptotic activity. A direct correlation may be shown between the overexpression of BCL-2 and the postponement of cell death. It has been determined that a change in the expression of BCL-2 is the root cause of a variety of malignancies, including lung, breast, melanoma, and chronic lymphocytic leukemia, multiple sclerosis, diabetes. In this review, we addressed the genetic information and structural homology of BCL-2 family members. Further, we elucidate the pro-apoptotic and anti-apoptotic roles of the family members. This review highlights the most recent developments in the BCL-2 protein family and presents evidence that targeting this family proteins may have a positive impact on the treatment of medical problems that are still underserved.

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Crosstalk between Noxa, Bcl-2, and ceramide in mediating p53-dependent apoptosis in Molt-4 human T-cell leukemia

Cited by 11 publications

References 40 publications

Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis

Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis

Design and Characterization of a Novel Venetoclax-Zanubrutinib Nano-Combination for Enhancing Leukemic Cell Uptake and Long-Acting Plasma Exposure

Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context

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