title: Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway.
abstract: We and others have shown that stresses, including photodynamic therapy (PDT), can disrupt the de novo sphingolipid biosynthesis pathway, leading to changes in the levels of sphingolipids, and subsequently, modulation of cell death. The de novo sphingolipid biosynthesis pathway includes a ceramide synthase-dependent reaction, giving rise to dihydroceramide, which is then converted in a desaturase-dependent reaction to ceramide. In this study we tested the hypothesis that combining Foscan-mediated PDT with desaturase inhibitor fenretinide (HPR) enhances cancer cell killing. We discovered that by subjecting SCC19 cells, a human head and neck squamous cell carcinoma cell line, to PDT+HPR resulted in enhanced accumulation of C16-dihydroceramide, not ceramide. Concomitantly, mitochondrial depolarization was enhanced by the combined treatment. Enhanced activation of caspase-3 after PDT+HPR was inhibited by FB. Enhanced clonogenic cell death after the combination was sensitive to FB, as well as Bcl2- and caspase inhibitors. Treatment of mouse SCCVII squamous cell carcinoma tumors with PDT+HPR resulted in improved long-term tumor cures. Overall, our data showed that combining PDT with HPR enhanced apoptotic cancer cell killing and antitumor efficacy of PDT. The data suggest the involvement of the de novo sphingolipid biosynthesis pathway in enhanced apoptotic cell killing after PDT+HPR, and identify the combination as a novel more effective anticancer treatment than either treatment alone.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
authors.forename: Nithin B
authors.initials: NB
authors.lastname: Boppana
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: DeLor
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI 48201, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Buren
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Pierce
authors.affiliation: British Columbia Cancer Agency, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada.
authors.forename: Mladen
authors.initials: M
authors.lastname: Korbelik
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA; Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI 48201, USA. Electronic address: dseparovic@wayne.edu.
authors.forename: Duska
authors.initials: D
authors.lastname: Separovic
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D017313:Fenretinide / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008652:Mesoporphyrins / Q000008:administration & dosage / Q000627:therapeutic use*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D013107:Sphingolipids / Q000096:biosynthesis*
chemical_list: D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D013107:Sphingolipids; D017313:Fenretinide; C072269:temoporfin
keywords: Apoptosis; Desaturase; Dihydroceramide; Fenretinide; PDT; Sphingolipids