Author:

Keywords:

Animals, activated protein-kinase, Apoptosis, n-terminal kinase, kappa-b activation, Humans, human-immunodeficiency-virus, Perylene, Photochemotherapy, ice/ced-3 family proteases, determine cell-death, Research Support, Non-U.S. Gov't, cytochrome-c, Signal Transduction, hela-cells, poly(adp-ribose) polymerase, antiretroviral activity, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, ACTIVATED PROTEIN-KINASE, N-TERMINAL KINASE, KAPPA-B ACTIVATION, HUMAN-IMMUNODEFICIENCY-VIRUS, ICE/CED-3 FAMILY PROTEASES, DETERMINE CELL-DEATH, CYTOCHROME-C, HELA-CELLS, POLY(ADP-RIBOSE) POLYMERASE, ANTIRETROVIRAL ACTIVITY, Anthracenes, 0601 Biochemistry and Cell Biology, 3101 Biochemistry and cell biology

Abstract:

Investigation of the molecular mechanisms underlying hypericin photocytotoxicity in cancer cells has revealed that this photosensitizer can induce both apoptosis and necrosis in a concentration- and light dose- dependent fashion. From this study it is clear that PDT with hypericin results in the activation of multiple pathways that either positively or negatively regulate cell death (schematically depicted in Fig. 10). PDT- induced apoptosis is mediated by a mitochondria-regulated pathway involving the release of cytochrome c in the cytosol and the further activation of the effector pro-caspase-3. In addition, hypericin induces the sustained activation of the JNK and p38 MAPK pathways that functionally cooperate in delaying cell death, probably by the induction of the transcription of survival-promoting genes. However, the concomitant irreversible inhibition of the growth-promoting ERK-signaling system may counterbalance this protective response leading to cell death commitment. The identification of these relevant components of the PDT-induced pro- and anti-apoptotic pathways provides an important starting, point to further identify and characterize other mediators of these signaling cascades. The observation that JNK and p38 MAPK inhibition enhances the PDT-induced cell death may offer molecular bases for the development of new therapeutic strategies to enhance the effectiveness of hypericin as an anticancer tool in PDT.