title: Increased tumour dihydroceramide production after Photofrin-PDT alone and improved tumour response after the combination with the ceramide analogue LCL29. Evidence from mouse squamous cell carcinomas.
abstract: Photodynamic therapy (PDT) has been proven effective for treatment of several types of cancer. Photodynamic therapy alone, however, attains limited cures with some tumours and there is need for its improved efficacy in such cases. Sphingolipid (SL) analogues can promote tumour response in combination with anticancer drugs. In this study, we used mouse SCCVII squamous cell carcinoma tumours to determine the impact of Photofrin-PDT on the in vivo SL profile and the effect of LCL29, a C6-pyridinium ceramide, on PDT tumour response. Following PDT, the levels of dihydroceramides (DHceramides), in particular C20-DHceramide, were elevated in tumours. Similarly, increases in DHceramides, in addition to C20:1-ceramide, were found in PDT-treated SCCVII cells. These findings indicate the importance of the de novo ceramide pathway in Photofrin-PDT response not only in cells but also in vivo. Notably, co-exposure of SCCVII tumours to Photofrin-PDT and LCL29 led to enhanced tumour response compared with PDT alone. Thus, we show for the first time that Photofrin-PDT has a distinct signature effect on the SL profile in vitro and in vivo, and that the combined treatment advances PDT therapeutic gain, implying translational significance of the combination.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA. dseparovic@wayne.edu
authors.forename: D
authors.initials: D
authors.lastname: Separovic
authors.forename: J
authors.initials: J
authors.lastname: Bielawski
authors.forename: J S
authors.initials: JS
authors.lastname: Pierce
authors.forename: S
authors.initials: S
authors.lastname: Merchant
authors.forename: A L
authors.initials: AL
authors.lastname: Tarca
authors.forename: B
authors.initials: B
authors.lastname: Ogretmen
authors.forename: M
authors.initials: M
authors.lastname: Korbelik
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002518:Ceramides / Q000378:metabolism* / Q000627:therapeutic use*; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D051379:Mice; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D010778:Photochemotherapy; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D013107:Sphingolipids / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C539200:2-N-(6'-(1''-pyridinium)hexanoyl)sphingosine; D000970:Antineoplastic Agents; D002518:Ceramides; D011726:Pyridinium Compounds; D013107:Sphingolipids; C109343:dihydroceramide; D017323:Dihematoporphyrin Ether