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Photodynamic Therapy Combined with Bcl-2/Bcl-xL Inhibition Increases the Noxa/Mcl-1 Ratio Independent of Usp9X and Synergistically Enhances Apoptosis in Glioblastoma

2021; Multidisciplinary Digital Publishing Institute; Volume: 13; Issue: 16 Linguagem: Inglês

10.3390/cancers13164123

2072-6694

Carolin Golla, Mayas Bilal, Annika Dwucet, Nicolas Bader, Jenson Anthonymuthu, Tim Heiland, Maximilian Pruss, Mike‐Andrew Westhoff, Markus D. Siegelin, Felix Capanni, Christian Rainer Wirtz, Richard E. Kast, Marc‐Eric Halatsch, Georg Karpel‐Massler,

Ocular Oncology and Treatments

The purpose of this study was to assess in vitro whether the biological effects of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy are enhanced by inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in different glioblastoma models. Pre-clinical testing of a microcontroller-based device emitting light of 405 nm wavelength in combination with exposure to 5-ALA (PDT) and the Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax) was performed in human established and primary cultured glioblastoma cells as well as glioma stem-like cells. We applied cell count analyses to assess cellular proliferation and Annexin V/PI staining to examine pro-apoptotic effects. Western blot analyses and specific knockdown experiments using siRNA were used to examine molecular mechanisms of action. Bcl-2/Bcl-xL inhibition synergistically enhanced apoptosis in combination with PDT. This effect was caspase-dependent. On the molecular level, PDT caused an increased Noxa/Mcl-1 ratio, which was even more pronounced when combined with ABT-263 in a Usp9X-independent manner. Our data showed that Bcl-2/Bcl-xL inhibition increases the response of glioblastoma cells toward photodynamic therapy. This effect can be partly attributed to cytotoxicity and is likely related to a pro-apoptotic shift because of an increased Noxa/Mcl-1 ratio. The results of this study warrant further investigation.