Investigate the Molecular Mechanisms Involved in Enhancing Photodynamic Thetapy Using an Old Antibiotic Agent

δ -aminolevulinic acid mediated photodynamic therapy (ALA-PDT) has been developed as a modality for cancer treatment, which is based on exogenous administration of ALA to produce the photosenstizer protoporphyrin IX (PpIX) via the heme biosynthesis pathway, and then irradiated the photosernsitizer to induce cytotoxicity. Previously, we have found that, combining doxycycline (DOXY) and ALA-PDT can exert a synergistic cytotoxic effect on human neurofibrosarcoma S462 cells, human malignant melanoma A375 cells, human lung adenocarcinoma cells (A549, CL1-5) and mice C26 adenocarcinoma cells after light irradiation. Further studies showed that such synergistic effect was due to the increased amount of PpIX in the cells in the presence of DOXY. However, the mechanisms of how DOXY and ALA-PDT combination resulting in synergistic cytotoxic effect upon light irradiation is still not clear. Therefore, the aims of this research proposal are to verify the molecular mechanisms involved in DOXY and ALA-PDT combination in cytotoxicity upon light irradiation, and to develop a pharmaceutical dosage form for future clinical application. The first aim is to elucidate how DOXY can synergistically increase ALA and/or PpIX content in cells and further investigate the molecular mechanisms involved. Understanding the mechanistic basis and molecular changes can portray a more complete picture of how DOXY can increase the therapeutic effect of ALA-PDT and therefore are of great clinical significance. The second aim is to apply the molecular findings to further develop a pharmaceutical dosage form containing ALA and DOXY.