Abstract
Pheophorbide a (Pa), a chlorophyll derivative, is a photosensitizer that can induce significant antitumor effects in several types of tumor cells. The present study investigated the mechanism of Pa-mediated photodynamic therapy (Pa-PDT) in the human skin cancer cell lines A431 and G361. PDT significantly inhibited the cell growth in a Pa-concentration-dependent manner. We observed increased expression of Beclin-1, LC3B and ATG5, which are markers of autophagy, after PDT treatment in A431 cells but not in G361 cells. In G361 cells, Pa-PDT strongly induced PARP cleavage and subsequent apoptosis, which was confirmed using Annexin V/Propidium iodide double staining. Pa-PDT predominantly exhibited its antitumor effects via activation of ERK1/2 and p38 in A431 and G361 cells, respectively. An in vivo study using the CAM xenograft model demonstrated that Pa-PDT strongly induced autophagy and apoptosis in A431-transplanted tumors and/or apoptosis in G361-transplanted tumors. These results may provide a basis for understanding the underlying mechanisms of Pa-PDT and for developing Pa-PDT as a therapy for skin cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis / radiation effects
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Apoptosis Regulatory Proteins / biosynthesis
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Autophagy / drug effects*
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Autophagy / radiation effects
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Autophagy-Related Protein 5
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Beclin-1
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / radiation effects
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Chlorophyll / analogs & derivatives*
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Chlorophyll / therapeutic use
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / radiation effects
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Membrane Potential, Mitochondrial / drug effects
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Membrane Proteins / biosynthesis
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Mice
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Microtubule-Associated Proteins / biosynthesis
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Photochemotherapy*
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Photosensitizing Agents / therapeutic use*
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Poly(ADP-ribose) Polymerases / metabolism
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Skin Neoplasms / drug therapy*
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Xenograft Model Antitumor Assays
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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ATG5 protein, human
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Apoptosis Regulatory Proteins
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Autophagy-Related Protein 5
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BECN1 protein, human
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Beclin-1
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MAP1LC3B protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Photosensitizing Agents
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Chlorophyll
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Poly(ADP-ribose) Polymerases
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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pheophorbide a