title: Enhanced tumor cures after Foscan photodynamic therapy combined with the ceramide analog LCL29. Evidence from mouse squamous cell carcinomas for sphingolipids as biomarkers of treatment response.
abstract: To improve anticancer therapeutic success of photodynamic therapy (PDT), combination treatments represent a viable strategy. Sphingolipid analogs combined with anticancer drugs can enhance tumor response. We have shown that LCL29, a C6-pyridinium ceramide, promotes therapeutic efficacy of Photofrin-PDT in mouse SCCVII squamous cell carcinoma tumors. The long-term effect of the combination PDT + LCL29 is unknown. In this study we used the same model to test the long-term curative potential of Foscan-PDT + LCL29. We show that treatment of SCCVII tumors with the combination led to enhanced long-term tumor cure compared to PDT alone. LCL29 itself did not prevent tumor growth. All treatments triggered early increases in tumor-associated C16-ceramide, C18-ceramide, dihydrosphingosine, and global levels of dihydroceramides. PDT-evoked increases in tumor-associated sphingosine-1-phosphate and dihydrosphingosine-1-phosphate remained elevated or were attenuated after the combination, respectively; in contrast, LCL29 had no effect on these two sphingolipids. Our data demonstrate that adjuvant LCL29 improves PDT long-term therapeutic efficacy, implying translational potential of the combination. Furthermore, our findings indicate that changes in the sphingolipid profile might serve as predictive biomarkers of tumor response to treatments.
authors.affiliation: Department of Pharmaceutical 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: G
authors.initials: G
authors.lastname: Bhatti
authors.forename: B
authors.initials: B
authors.lastname: Ogretmen
authors.forename: M
authors.initials: M
authors.lastname: Korbelik
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002518:Ceramides / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008652:Mesoporphyrins / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013107:Sphingolipids / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: C539200:2-N-(6'-(1''-pyridinium)hexanoyl)sphingosine; D015415:Biomarkers; D002518:Ceramides; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D011726:Pyridinium Compounds; D013107:Sphingolipids; C072269:temoporfin