Journal
ONCOTARGET
Volume 7, Issue 27, Pages 42374-42384Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9872
Keywords
non-Hodgkin's lymphoma; WSU-FSCCL; PNT2258; DNAi; apoptosis
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Funding
- ProNAi Therapeutics
- St John Hospital
- Medical Center Foundation
- Michigan Corporate Relations Network's (MCRN) Small Company Innovation Program (SCIP)
- NIH [P30CA022453]
- Perinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University
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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. 2.5 mu M 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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