Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines

Zangemeister‐Wittke, Uwe; Schenker, Thomas; Luedke, G H; Stahel, R.

doi:10.1038/bjc.1998.624

Cited by 128 publications

(58 citation statements)

References 23 publications

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“…For comparison, we also studied the clones expressing Bcl-2, which has been shown to increase resistance to etoposide (30,31). As expected, H526 clones overexpressing Bcl-2 show decreased sensitivity to etoposide compared with the empty vector control (Fig.…”

Section: Increased Noxa Expression Results In Increased Sensitivity Tmentioning

confidence: 99%

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

Hauck

Chao

Litz

et al. 2009

Molecular Cancer Therapeutics

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To understand the molecular basis for variable sensitivity to the BH3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of small cell lung cancer cell lines whose sensitivity varied over a 2-log range. Elevated Noxa and Bcl-2 levels directly correlated with sensitivity to ABT-737, whereas Mcl-1 levels were similar in all cell lines tested regardless of sensitivity. Transgenically enforced expression of Noxa but not Bcl-2 resulted in increased sensitivity to ABT-737 in multiple cell lines. This increase was especially pronounced in the H209 cell line in which expression of Noxa resulted in a proportionate decline in Mcl-1 expression. Although overexpression of Noxa enhanced sensitivity of the H526 and H82 cell lines to ABT-737, it did not result in altered Mcl-1 levels. Similarly, small interfering RNA-mediated knockdown of Noxa expression in the H146 cell line, which increased resistance to ABT-737, did not result in altered Mcl-1 levels. Therefore, three of four cell lines studied failed to show Noxa-mediated regulation of Mcl-1 expression. However, despite failure to regulate Mcl-1 levels, Noxa blocked binding of Bim to Mcl-1 following its release from Bcl-2 by ABT-737. Finally, we observed that a 24-hour incubation of the H526 and WBA cell lines with ABT-737 resulted in increased Noxa expression, suggesting that Noxa may play a direct role in ABT-737-mediated apoptosis. These results indicate that Noxa expression is the critical determinant of ABT-737 sensitivity and loss of Noxa-mediated regulation of Mcl-1 expression may be an important feature of small cell lung cancer biology. [Mol Cancer Ther 2009;8(4):883-92]

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Section: Increased Noxa Expression Results In Increased Sensitivity Tmentioning

confidence: 99%

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

Hauck

Chao

Litz

et al. 2009

Molecular Cancer Therapeutics

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show abstract

“…A synergistic antitumoral effect of bcl-2 antisense therapy combined with some anticancer agents has been demonstrated in leukemia and lung cancer cells overexpressing Bcl-2 (Zangemeister- Wittke et al, 1998;Konopleva et al, 2000;Miayake et al, 2000a).…”

Section: Bcl-2 Familymentioning

confidence: 99%

The future of antisense therapy: combination with anticancer treatments

Biroccio¹,

Leonetti²,

Zupi³

2003

Oncogene

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“…In contrast to previous reports (8,9) in which gene silencing was assessed in bulk cells by Western blot, a great advantage was obtained from a recently established flow cytometry procedure that simultaneously evaluates Bcl-2 knockdown and viability in SCLC cells (10).…”

mentioning

confidence: 87%

“…Although ODNs are still undergoing preclinical and clinical evaluation, other gene silencing molecules such as small interfering RNAs (siRNAs) are being used extensively in research both as powerful tools to decipher gene function and as promising therapeutic agents. The assessment of the therapeutic potential of anti-BCL2 gene silencing in SCLC has been restricted to the use of ODN (7)(8)(9), whereas no reports with siRNA are available. It is widely accepted that gene silencing therapies depend on the development of adequate nanocarriers to be used to achieve adequate intracellular delivery.…”

mentioning

confidence: 99%

In vitro modulation of Bcl-2 levels in small cell lung cancer cells: effects on cell viability

Santos

Pereira

Lima

et al. 2010

Braz J Med Biol Res

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Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines

Cited by 128 publications

References 23 publications

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

The future of antisense therapy: combination with anticancer treatments

In vitro modulation of Bcl-2 levels in small cell lung cancer cells: effects on cell viability

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