Photodynamic effects of novel 5,15-diaryl-tetrapyrrole derivatives on human colon carcinoma cells.
Preliminary in vitro cytotoxicity studies on a panel of meso diaryl-substituted tetrapyrrole derivatives newly synthesized in our laboratory have shown that these compounds are photodynamically active on the human colon carcinoma cell line HCT116. In the present study, we investigate some mechanistic aspects of the photodynamic action of the most active compounds in the series, namely the 5-phenyl-15-(3-methoxyphenyl)porphyrin (1), the 5-phenyl-15-(3-hydroxyphenyl)porphyrin (2) and the 5,15-diphenylporphyrin (3). The results of the cytotoxicity studies indicate that the novel photosensitisers (PSs) are more potent in vitro than m-THPC (Foscan), a powerful PS already approved for clinical use in photodynamic therapy (PDT). A series of experiments were performed to elucidate a number of aspects in the mechanism of PS-induced phototoxicity, including, intracellular accumulation and subcellular localization of the PSs, induction of apoptosis, and generation of reactive oxygen species (ROS) and NO*. All the compounds tested exhibit similar singlet oxygen quantum yields; differential intracellular accumulation can contribute to the observed differences in phototoxicity. Flow cytometric studies indicate that all the tested compounds induce apoptosis; however, their cytotoxic effect does not seem to rely solely on this process. Generation of significant amounts of reactive oxygen species (ROS) and NO* were also observed; however, the contribution of this latter effect to the overall phototoxicity is unclear. Taken together, our observations suggest that the diaryl derivatives included in the present study could represent promising leads for the development of novel photosensitizing agents.
Gariboldi
Marzia B
MB
DBSF-Section of Pharmacology, University of Insubria, Busto Arsizio, VA, Italy.
Ravizza
Raffaella
R
Baranyai
Peter
P
Caruso
Enrico
E
Banfi
Stefano
S
Meschini
Stefania
S
Monti
Elena
E
D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000633:toxicity*; D011166:Porphyrins / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D026082:Singlet Oxygen / Q000378:metabolism
C540777:5,15-diphenylporphyrin; C540818:5-phenyl-15-(3-hydroxyphenyl)porphyrin; C540776:5-phenyl-15-(3-methoxyphenyl)porphyrin; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; D026082:Singlet Oxygen; D009569:Nitric Oxide