TY - JOUR
T1 - Induction of apoptosis by G3139 in melanoma cells.
AU - Benimetskaya, Luba
AU - Lai, Johnathan C.
AU - Khvorova, Anastasia
AU - Wu, Sijian
AU - Miller, Paul
AU - Stein, C. A.
N1 - Copyright:
This record is sourced from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
PY - 2005/11
Y1 - 2005/11
N2 - G3139 is an 18mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. Because of the ability of this antisense construct to downregulate the expression of Bcl-2 mRNA and protein, it has entered phase III clinical trials in a number of human cancers, including advanced melanoma. However, the actual mechanism of this agent is far from certain. In this work, we demonstrate that G3139 induces the relatively rapid release of cytochrome c into the cytoplasm of treated 518A2 melanoma cells. This release activates the intrinsic pathway of apoptosis, eventually leading to a mitochondrial permeability transition and cell death. By employing an siRNA strategy, we also show that this entire process appears to be Bcl-2 independent, as downregulation of Bcl-2 protein expression does not alter the induction of apoptosis by G3139. Furthermore, forced overexpression of Bcl-2 protein contributes relatively little to chemoresistance in this cell line. While these results may or may not be reflective of the in vivo situation, the value of Bcl-2 as a target in advanced melanoma must at least be questioned.
AB - G3139 is an 18mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. Because of the ability of this antisense construct to downregulate the expression of Bcl-2 mRNA and protein, it has entered phase III clinical trials in a number of human cancers, including advanced melanoma. However, the actual mechanism of this agent is far from certain. In this work, we demonstrate that G3139 induces the relatively rapid release of cytochrome c into the cytoplasm of treated 518A2 melanoma cells. This release activates the intrinsic pathway of apoptosis, eventually leading to a mitochondrial permeability transition and cell death. By employing an siRNA strategy, we also show that this entire process appears to be Bcl-2 independent, as downregulation of Bcl-2 protein expression does not alter the induction of apoptosis by G3139. Furthermore, forced overexpression of Bcl-2 protein contributes relatively little to chemoresistance in this cell line. While these results may or may not be reflective of the in vivo situation, the value of Bcl-2 as a target in advanced melanoma must at least be questioned.
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U2 - 10.1196/annals.1359.033
DO - 10.1196/annals.1359.033
M3 - Review article
C2 - 16394140
AN - SCOPUS:33745314890
VL - 1058
SP - 235
EP - 245
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
SN - 0077-8923
ER -