Induction of apoptosis by G3139 in melanoma cells.

Luba Benimetskaya, Johnathan C. Lai, Anastasia Khvorova, Sijian Wu, Paul Miller, C. A. Stein

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)235-245
Number of pages11
JournalAnnals of the New York Academy of Sciences
Volume1058
DOIs
StatePublished - Nov 2005
Externally publishedYes

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Melanoma
Apoptosis
Down-Regulation
Phosphorothioate Oligonucleotides
Phase III Clinical Trials
Messenger RNA
Proteins
Initiator Codon
Cell death
Cytochromes c
Small Interfering RNA
Permeability
Cytoplasm
Cell Death
Cells
Cell Line
oblimersen
Protein
Induction
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Benimetskaya, L., Lai, J. C., Khvorova, A., Wu, S., Miller, P., & Stein, C. A. (2005). Induction of apoptosis by G3139 in melanoma cells. Annals of the New York Academy of Sciences, 1058, 235-245. https://doi.org/10.1196/annals.1359.033

Induction of apoptosis by G3139 in melanoma cells. / Benimetskaya, Luba; Lai, Johnathan C.; Khvorova, Anastasia; Wu, Sijian; Miller, Paul; Stein, C. A.

In: Annals of the New York Academy of Sciences, Vol. 1058, 11.2005, p. 235-245.

Research output: Contribution to journalArticle

Benimetskaya, L, Lai, JC, Khvorova, A, Wu, S, Miller, P & Stein, CA 2005, 'Induction of apoptosis by G3139 in melanoma cells.', Annals of the New York Academy of Sciences, vol. 1058, pp. 235-245. https://doi.org/10.1196/annals.1359.033
Benimetskaya L, Lai JC, Khvorova A, Wu S, Miller P, Stein CA. Induction of apoptosis by G3139 in melanoma cells. Annals of the New York Academy of Sciences. 2005 Nov;1058:235-245. https://doi.org/10.1196/annals.1359.033
Benimetskaya, Luba ; Lai, Johnathan C. ; Khvorova, Anastasia ; Wu, Sijian ; Miller, Paul ; Stein, C. A. / Induction of apoptosis by G3139 in melanoma cells. In: Annals of the New York Academy of Sciences. 2005 ; Vol. 1058. pp. 235-245.
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