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1 July 2003 Association Between the Photodynamic Loss of Bcl-2 and the Sensitivity to Apoptosis Caused by Phthalocyanine Photodynamic Therapy
Jitsuo Usuda, Kashif Azizuddin, Song-mao Chiu, Nancy L. Oleinick
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We have reported that photodynamic therapy (PDT) using the photosensitizer phthalocyanine (Pc) 4 and red light damages the antiapoptotic protein Bcl-2. Recently, using transient transfection of Bcl-2 deletion mutants, we identified the membrane anchorage domains of Bcl-2 as necessary to form the photosensitive target. However, it is not clear how Bcl-2 photodamage sensitizes cells to Pc 4-PDT–induced apoptosis, whether overall cell killing is also sensitized or how upregulation of Bcl-2 in tumors might make them more or less responsive to Pc 4-PDT. In this study we report on MCF-7c3 cells (human breast cancer cells expressing stably transfected procaspase-3) overexpressing wild-type Bcl-2 or certain deletion mutants in either a transient or a stable mode. By flow cytometric analysis of transiently transfected cells, we found that wild-type Bcl-2, Bcl-2Δ33-54 and Bcl-2Δ37-63 (each of which can be photodamaged) protected cells from apoptosis caused by Pc 4-PDT. In contrast, Bcl-2Δ210-239, which lacks the C-terminal transmembrane domain and cannot be photodamaged, afforded no protection. We then evaluated the PDT sensitivity of transfected cell lines stably overexpressing high levels of wild-type Bcl-2 or one of the Bcl-2 mutants. Overexpression of wild-type Bcl-2, Bcl-2Δ33-54 or Bcl-2Δ37-63 resulted in relative resistance of cells to Pc 4-PDT, as assessed by morphological apoptosis or loss of clonogenicity. Furthermore, overexpression of Bcl-2 also inhibited the activation-associated conformational change of the proapoptotic protein Bax, and higher doses of Pc 4 and light were required to activate Bax in cells expressing high levels of Bcl-2. Many advanced cancer cells have elevated amounts of Bcl-2. Our results show that increasing the dose of Pc 4-PDT can overcome the resistance afforded by either Bcl-2 or the two mutants. PDT regimens that photodamage Bcl-2 lead to activation of Bax, induction of apoptosis and elimination of the otherwise resistant tumor cells.

Jitsuo Usuda, Kashif Azizuddin, Song-mao Chiu, and Nancy L. Oleinick "Association Between the Photodynamic Loss of Bcl-2 and the Sensitivity to Apoptosis Caused by Phthalocyanine Photodynamic Therapy," Photochemistry and Photobiology 78(1), 1-8, (1 July 2003).<0001:ABTPLO>2.0.CO;2
Received: 18 March 2003; Accepted: 1 April 2003; Published: 1 July 2003

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