title: Structure-activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cells.
abstract: The photobehavior of ciprofloxacin, lomefloxacin and ofloxacin fluoroquinolones was investigated using several in vitro methods to assess their cytotoxic, antiproliferative, and genotoxic potential against two human cancer cell lines. We focused our attention on the possible relationship between their chemical structure, O₂ partial pressure and photobiological activity on cancer cells. The three molecules share the main features of most fluoroquinolones, a fluorine in 6 and a piperazino group in 7, but differ at the key position 8, unsubstituted in ciprofloxacin, a fluorine in lomefloxacin and an alkoxy group in ofloxacin. Studies in solution show that ofloxacin has a low photoreactivity; lomefloxacin reacts via aryl cation, ciprofloxacin reacts but not via the cation. In our experiments, ciprofloxacin and lomefloxacin showed a high and comparable potential for photodamaging cells and DNA. Lomefloxacin appeared the most efficient molecule in hypoxia, acting mainly against tumour cell proliferation and generating DNA plasmid photocleavage. Although our results do not directly provide evidence that a carbocation is involved in photodamage induced by lomefloxacin, our data strongly support this hypothesis. This may lead to new and more efficient anti-tumour drugs involving a cation in their mechanism of action. This latter acting independently of oxygen, can target hypoxic tumour tissue.
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Perucca
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Savio
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cazzalini
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mocchi
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccario
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sommatis
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferraro
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pizzala
authors.affiliation: Dipartimento di Chimica, Viale Taramelli 12, University of Pavia, 27100 Pavia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pretali
authors.affiliation: Dipartimento di Chimica, Viale Taramelli 12, University of Pavia, 27100 Pavia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fasani
authors.affiliation: Dipartimento di Chimica, Viale Taramelli 12, University of Pavia, 27100 Pavia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Albini
authors.affiliation: Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia Generale, Via Ferrata 9, University of Pavia, 27100 Pavia, Italy. Electronic address: luciaanna.stivala@unipv.it.
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Stivala
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002939:Ciprofloxacin / Q000737:chemistry / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D024841:Fluoroquinolones / Q000737:chemistry* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D010100:Oxygen / Q000737:chemistry*; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000633:toxicity; D010957:Plasmids / Q000187:drug effects / Q000378:metabolism; D026082:Singlet Oxygen / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
chemical_list: D024841:Fluoroquinolones; D017319:Photosensitizing Agents; D026082:Singlet Oxygen; D002939:Ciprofloxacin; C053091:lomefloxacin; D010100:Oxygen
keywords: Anticancer drugs; Apoptosis; DNA damage; Fluoroquinolones; UVA