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.
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.
Lymphoma Research Lab, Wayne State University, Detroit, MI, 48201-USA.
Abdul Shukkur
AS
Ebrahim
Department of Pathology, Wayne State University, Detroit, MI, 48201-USA.
Mustapha
M
Kandouz
Lymphoma Research Lab, Wayne State University, Detroit, MI, 48201-USA.
Allison
A
Liddane
Lymphoma Research Lab, Wayne State University, Detroit, MI, 48201-USA.
Hussam
H
Sabbagh
Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI, 48201-USA.
Yuning
Y
Hou
Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI, 48201-USA.
Chunying
C
Li
Lymphoma Research Lab, Wayne State University, Detroit, MI, 48201-USA.
Ayad
A
Al-Katib
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase; D014178:Translocation, Genetic
D008081:Liposomes; D009838:Oligodeoxyribonucleotides; C000588986:PNT100; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C505407:CASP3 protein, human; D053148:Caspase 3
DNAi; PNT2258; WSU-FSCCL; apoptosis; non-Hodgkin’s lymphoma