Oncotarget

Research Papers:

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

Abdul Shukkur Ebrahim _, Mustapha Kandouz, Allison Liddane, Hussam Sabbagh, Yuning Hou, Chunying Li and Ayad Al-Katib

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Oncotarget. 2016; 7:42374-42384. https://doi.org/10.18632/oncotarget.9872

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Abstract

Abdul Shukkur Ebrahim1, Mustapha Kandouz2, Allison Liddane1, Hussam Sabbagh1, Yuning Hou3, Chunying Li3, Ayad Al-Katib1

1Lymphoma Research Lab, Wayne State University, Detroit, MI, 48201-USA

2Department of Pathology, Wayne State University, Detroit, MI, 48201-USA

3Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI, 48201-USA

Correspondence to:

Ayad Al-Katib, e-mail: aa1526@wayne.edu

Keywords: non-Hodgkin’s lymphoma, WSU-FSCCL, PNT2258, DNAi, apoptosis

Received: November 14, 2015    Accepted: May 11, 2016    Published: June 7, 2016

ABSTRACT

Current therapy for BCL-2-associated tumors such as Non-Hodgkin Lymphomas (NHL) is inadequate. The DNAi PNT2258, a 24 base single-stranded phosphodiester DNA oligodeoxynucleotide (PNT100) encapsulated in a protective liposome, was precisely designed to treat cancers that over-express BCL-2. PNT2258 strongly inhibited BCL-2 promoter activity, confirming its predicted mechanism of action. BCL-2 mRNA and protein expression were significantly downregulated in a follicular small cleaved cell lymphoma (WSU-FSCCL) cell line. 2.5μM PNT2258 induced an initial S- phase arrest followed by a gradual increase in the sub-G0 (apoptosis) compartment and a reciprocal progressive decrease of the S phase. Terminal deoxynucleotidyl transferase (TdT)-positive populations and cleaved caspase-3 and PARP were also increased. The data are consistent with the idea that BCL-2 inhibition by PNT2258 activates apoptotic pathways in WSU-FSCCL cells. This is the first report to address the distinct mechanism of action underlying the anti-BCL-2 functions of PNT2258. Growth inhibition in two other cell lines, WSU-DLCL2 and WSU-WM, supports broad applicability of BCL-2 DNAi to treatment of B-cell NHL.


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