title: Combining anticancer agents photodynamic therapy and LCL85 leads to distinct changes in the sphingolipid profile, autophagy, caspase-3 activation in the absence of cell death, and long-term sensitization.
abstract: Two anticancer agents, LCL85 and photodynamic therapy (PDT) were combined to test whether the combination PDT/LCL85 evokes changes in the sphingolipid (SL) profile and promotes cell death. Treatment of SCCVII mouse squamous carcinoma cells using the silicone phthalocyanine Pc 4 for PDT induced increases in the prodeath global ceramides/dihydroceramides (DHceramides), and no changes in the prosurvival sphingosine-1-phosphate (S1P). In contrast, after LCL85, the levels of most ceramides and DHceramides were reduced, whereas the levels of S1P were increased. After PDT/LCL85 the levels of global ceramides and DHceramides, and of S1P, were restored to resting levels. PDT/LCL85 also enhanced the levels of C18-, C20-, and C20:1-ceramide, and C18-DHceramide. Treatment with PDT, with or without LCL85, led to substantial reductions in sphingosine levels. PDT/LCL85 induced enhanced autophagy and caspase-3 activation. None of the treatments affected short-term viability of cells. In contrast, long-term clonogenic survival was reduced not only after PDT or LCL85, but even more after PDT/LCL85. Overall, our data show that short-term exposure to PDT/LCL85 led to distinct signature effects on the SL profile, enhanced autophagy, and caspase-3 activation without cell death. Long-term exposure to PDT/LCL85 enhanced overall cell killing, supporting translational potential of PDT/LCL85.
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: Duska
authors.initials: D
authors.lastname: Separovic
authors.forename: Nicholas
authors.initials: N
authors.lastname: Joseph
authors.forename: Paul
authors.initials: P
authors.lastname: Breen
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Jason S
authors.initials: JS
authors.lastname: Pierce
authors.forename: Eric Van
authors.initials: EV
authors.lastname: Buren
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatti
authors.forename: Ziad H
authors.initials: ZH
authors.lastname: Saad
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011412:Propanolamines / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C560215:2-N-(16-(1'-pyridinium)hexadecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol; D000970:Antineoplastic Agents; D002518:Ceramides; D007211:Indoles; D008246:Lysophospholipids; D017319:Photosensitizing Agents; D011412:Propanolamines; D011726:Pyridinium Compounds; D013107:Sphingolipids; C107448:phthalocyanine Pc 4; C060506:sphingosine 1-phosphate; D053148:Caspase 3; D013110:Sphingosine