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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.
AuthorsDuska Separovic, Nicholas Joseph, Paul Breen, Jacek Bielawski, Jason S Pierce, Eric Van Buren, Gaurav Bhatti, Ziad H Saad, Aiping Bai, Alicja Bielawska
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 409 Issue 3 Pg. 372-7 (Jun 10 2011) ISSN: 1090-2104 [Electronic] United States
PMID21545791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2011 Elsevier Inc. All rights reserved.
Chemical References
  • 2-N-(16-(1'-pyridinium)hexadecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol
  • Antineoplastic Agents
  • Ceramides
  • Indoles
  • Lysophospholipids
  • Photosensitizing Agents
  • Propanolamines
  • Pyridinium Compounds
  • Sphingolipids
  • phthalocyanine Pc 4
  • sphingosine 1-phosphate
  • Caspase 3
  • Sphingosine
Topics
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Autophagy
  • Carcinoma, Squamous Cell (drug therapy, metabolism)
  • Caspase 3 (metabolism)
  • Cell Line, Tumor
  • Ceramides (metabolism)
  • Head and Neck Neoplasms (drug therapy, metabolism)
  • Humans
  • Indoles (therapeutic use)
  • Lysophospholipids (metabolism)
  • Mice
  • Photochemotherapy
  • Photosensitizing Agents (therapeutic use)
  • Propanolamines (therapeutic use)
  • Pyridinium Compounds (therapeutic use)
  • Sphingolipids (metabolism)
  • Sphingosine (analogs & derivatives, metabolism)

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