Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin
2017
Abstract The low curative response to current treatment regimens for most
soft tissue sarcomasindicates a strong need for alternative treatment strategies and
predictive markersfor treatment outcome. PCI (
photochemical internalization) is a novel treatment strategy to translocate drugs into cytosol that otherwise would have been degraded in lysosomes. Two highly geno-and phenotypically different uterine and vulvar
leiomyosarcomacell lines, MES-SA and SK-LMS-1, were treated with bleomycin (BLM) activated by PCI (PCI BLM ). The MES-SA cells were much more sensitive to PCI BLM than the SK-LMS-1 cells and the treatment induced a 7–8 fold higher increase in DNA double-strand breaks at the same dose of light as measure by γH2AX staining. A 3-fold higher induction of apoptosis and stronger activation of Bax and p21 was also measured in the P53WT MES-SA cells, compared to the P53mut SK-LMS-1 cells. The basal formation of reactive oxygen species (ROS) was 3-fold higher in SK-LMS-1 cells than in the MES-SA cells and SK-LMS-1 cells expressed glutathione peroxidase 1 (
GPx1) and more superoxide dismutase 2 (
SOD2) than the MES-SA cells. Glutathione depletion with the
glutathione synthetaseinhibitor
buthionine sulfoximineincreased the cytotoxic effect of the photochemical treatment (PDT) most strongly in the SK-LMS-1 cells, and reduced PCI BLM -induced H2AX activation in the MES-SA cells, but not in the SK-LMS-1 cells. The results indicate PCI BLM as a potential novel treatment strategy for
soft tissue sarcomas, with antioxidant enzymes, in particular
GPx1, and the P53 status as potential
predictive markersfor response to PCI BLM .
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