PNT2258, a novel deoxyribonucleic acid inhibitor, induces cell cycle arrest and apoptosis via a distinct mechanism of action: a new class of drug for non-Hodgkin's lymphoma

Ebrahim, Abdul Shukkur; Kandouz, Mustapha; Liddane, Allison; Sabbagh, Hussam; Hou, Yuning; Li, Chunying; Al‐Katib, Ayad

doi:10.18632/oncotarget.9872

Cited by 31 publications

(33 citation statements)

References 49 publications

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“…The first approaches to inhibit BCL2 in the 1990s were based on antisense molecules and some of these, for example Oblimersen (Advani et al , ) PNT2258 (Ebrahim et al , ) and SPC2996 (Durig et al , ) entered clinical trials as outlined below. More recently, the field has advanced more successfully by targeting the proteins themselves.…”

Section: Bcl2 Family Members As Therapeutic Targetsmentioning

confidence: 99%

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Targeting anti‐apoptotic BCL2 family proteins in haematological malignancies – from pathogenesis to treatment

2017

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The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-X (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics. The first BCL2-specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia (CLL), with surprisingly little toxicity given the expression of BCL2 in normal tissues. Despite success in CLL, where sensitivity to BCL2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B-cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL2 inhibition. In this review, we summarise the biology of BCL2 proteins, the mechanism of action of BH3-mimetics and the status of their clinical development in haematological malignancies.

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Section: Bcl2 Family Members As Therapeutic Targetsmentioning

confidence: 99%

“…Another approach has been to target the BCL2 promoter. PNT2258 contains a single stranded 24‐base oligonucleotide complementary to the BCL2 promoter, resulting in inhibition of BCL2 transcription (Ebrahim et al , ).…”

Section: Portraits Of Selected Putative and Validated Molecules Targementioning

confidence: 99%

Targeting anti‐apoptotic BCL2 family proteins in haematological malignancies – from pathogenesis to treatment

2017

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“…WSU-WM-parent, -CD34 + , and -CD34cells were collected and centrifuged twice in cold PBS. Cells were then fixed in 5 ml of 70% ethanol and stored at 4°C overnight [17]. Cells were centrifuged and resuspended in 1 ml of staining buffer containing 50 ug/ml propidium iodide, 100 ug/ml of RNase A, and 0.1% of Triton X-100.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…Cells were seeded at a density of 0.2 × 10 6 viable cells/mL per well in a 24-well plate (Costar, Cambridge, MA, USA) for variable periods of time. The number of viable cells was determined by trypan blue exclusion (Sigma Chemical Co. St. Louis, MO, USA) at 24 hour intervals [17].…”

Section: Cell Count and Viabilitymentioning

confidence: 99%

“…Cells were harvested, washed in PBS and lysed in M-PER lysis buffer containing a protease and phosphatase inhibitor cocktail (Thermo Scientific, Rockford, IL, USA) [17]. Equal amounts of protein lysates were subjected to SDS-PAGE followed by blotting with the indicated antibodies and detection by Western Super Signal West Pico Chemiluminescent substrate reagents (Thermo Scientific, Rockford, IL, USA).…”

Section: Immunoblottingmentioning

confidence: 99%

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Isolation and characterization of a CD34+ sub-clone in B-cell lymphoma

et al. 2020

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Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in the US. Many types remain incurable despite response to initial therapy and achievement of complete remission (CR). Advanced laboratory techniques like multicolor flow cytometry (FCM) and polymerase chain reaction (PCR) have demonstrated persistence of rare malignant cell population post therapy. However, the functional and biological characteristics of this population have not been elucidated. Established B-lymphoma cell lines (B-NHL) and patient-derived samples (PDS) were analyzed using 8-color FCM. CD34 + sub-population was enriched using in vitro exposure to 2-chlorodeoxyadenosine (2-CdA) and by CD34 magnetic beads. Genetic analysis of cell fractions was done by karyotyping and array comparative genomic hybridization (aCGH). Sensitivity to chemotherapy was assayed by short-term in vitro exposure to chemotherapy. Clonogenicity was determined by soft agar colony formation assay, and proliferation was determined using DNA staining with propidium iodide and FCM. FCM demonstrated the presence of a minute sub-clone of monotypic B-cells that express CD34 in B-NHL cell lines (3 of 3) and in PDS (8 of 8). This sub-population enriched up to 50 fold in vitro by exposure to 2-CdA and up to 80% purity by CD34 magnetic bead column isolation. Except for CD34 expression, this population expressed identical phenotype and genotype to parent cells, but was more proliferative, Hoechst 33342-positive, clonogenic, and resistant to chemotherapy compared with the CD34population. The isolated CD34 + monotypic B-cells may contribute to resistance of certain NHL to treatment and should be targeted by potential new drugs for NHL.

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Engineering Gene Therapy: Advances and Barriers

Shahryari

Burtscher

Nazari

et al. 2021

Advanced Therapeutics

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Currently, 33 gene‐therapy drugs/products have been approved in the clinic. Over 3000 completed and ongoing clinical gene therapy trials have been reported worldwide. The development/maturation of tools for gene manipulation and gene delivery, as well as molecular advances in the diagnosis of genetic diseases, have played a central role in gene therapy, which have greatly revolutionized the field. Versatile and diverse genetic tools for gene manipulations and deliveries, with the possibility of short and long‐term effects, are vital advantages of gene therapy tools, paving the road for the development of new therapies. However, efficacy and safety concerns, immune system responses, laborious approaches for developing and manufacturing, unknown gene‐therapy drug interactions with the host and the high cost of drugs/products, are significant barriers in gene therapy. Here, the authors review the attempts for engineering of the gene manipulations that have been undertaken in the last three decades and used in clinical trials focusing on 1) gene‐editing platforms, 2) viral gene delivery systems, and 3) nonviral gene tools. In this comprehensive review, the principles of these gene manipulation tools as well as advances and barriers for their application in modern therapies are discussed. Furthermore, trends and future directions in gene therapy are discussed.

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PNT2258, a novel deoxyribonucleic acid inhibitor, induces cell cycle arrest and apoptosis via a distinct mechanism of action: a new class of drug for non-Hodgkin's lymphoma

Cited by 31 publications

References 49 publications

Targeting anti‐apoptotic BCL2 family proteins in haematological malignancies – from pathogenesis to treatment

Targeting anti‐apoptotic BCL2 family proteins in haematological malignancies – from pathogenesis to treatment

Isolation and characterization of a CD34+ sub-clone in B-cell lymphoma

Engineering Gene Therapy: Advances and Barriers

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