TITLE

Enhancement of radiation sensitivity with BH3I-1 in non-small cell lung cancer

AUTHOR(S)
W., Roa; Chen H.; A., Alexander; S., Gulavita; J., Th'ng; X. J., Sun; K., Petruk; R., Moore
PUB. DATE
April 2005
SOURCE
Clinical & Investigative Medicine;Apr2005, Vol. 28 Issue 2, p55
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, are frequently over-expressed in human malignancies, and this is correlated with resistance to chemotherapeutic drugs and γ- radiation. Recently identified small organic molecules capable of inhibiting Bcl-2 and/or Bcl-xL function, may enhance radiation sensitivity of cancer cells in which they are over expressed. We examined whether specific blockade of the BH3-domain binding to Bcl-xL could sensitize cancer cells to γ- radiation. Methods: Human non-small-cell lung cancer H460 cells with wild-type p53 and H1792 cells with mutant p53 were exposed to various doses of radiation and/or BH3I-1 and for different points of time to BH3I-1 treatment. XTT and clonogenic survival assays were used to evaluate the growth-inhibitory effects of the antagonist BH3I-1, ionizing radiation or both. Western blot analysis was used to examine the cellular effect of the expression of Bcl-xL, Bax, and p53. Apoptosis and cell cycle distribution were analyzed by confocal microscopy with Hoechst 33258 staining and cytochrome c, and flow cytometry, respectively. Results: BH3I-1 appeared to induce a dose- and time-dependent apoptosis in H460 and H1792 cells, regardless of p53 status. After 2 days of BH3I-1 treatment, the cells that remained attached were exposed to ionizing radiation. Followed by clonogenic assay, BH3I-1 treatment enhanced the radiation sensitivity of H1792 surviving cells with mutant p53, but not in H460 cells with wild-type p53. A transient time-dependent cell cycle blockade at G2-M phase was identified for H1792 cells without subsequent modification of cell cycle distribution. Conclusion: These findings suggest a potential role for the small molecule inhibitor as a novel radiation sensitizer in non-small cell lung cancer.
ACCESSION #
16840130

 

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