title: Cationic ceramides and analogues, LCL30 and LCL85, as adjuvants to photodynamic therapy of tumors.
abstract: Photodynamic therapy (PDT) is known to alter the expression of various genes in treated cells. This prompted us to examine the activity of genes encoding two important enzymes in sphingolipid (SL) metabolism, dihydroceramide desaturase (DES) and sphingosine kinase (SPHK), in mouse SCCVII tumor cells treated by PDT using either the porphyrin-based photosensitizer Photofrin or silicon phthalocyanine Pc4. The results revealed that PDT induced an upregulation in the expression of two major isoforms of both genes (DES1 and DES2 as well as SPHK1 and SPHK2). While the changes were generally moderate (2-3-fold gains), the increase in DES2 expression was more pronounced and it was much greater with Photofrin-PDT than with Pc4-PDT (over 23-fold vs. less than 5-fold). Combining either Photofrin-PDT or Pc4-PDT with the cationic C16-ceramide LCL30 (20mg/kg i.p.) for treatment of subcutaneously growing SCCVII tumors rendered important differences in the therapy outcome. Photofrin-PDT, used at a dose that attained good initial response but no tumor cures, produced 50% cures when combined with a single LCL30 treatment. In contrast, the same LCL30 treatment combined with Pc4-PDT had no significant effect on tumor response. The optimal timing of LCL30 injection was immediately after Photofrin-PDT. The therapeutic benefit was lost when LCL30 was given in two 20mg/kg injections encompassing intervals before and after PDT. LCL85, the cationic B13 ceramide analogue and SL-modulating agent, also increased cure rates of Photofrin-PDT treated tumors, but the therapeutic benefit was less pronounced than with LCL30. These results with LCL30 and LCL85, and our previous findings for LCL29 (another SL analogue), assert the potential of SLs for use as adjuvants to augment the efficacy of PDT-mediated tumor destruction.
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada. mkorbelik@bccrc.ca
authors.forename: Mladen
authors.initials: M
authors.lastname: Korbelik
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Kyi Min
authors.initials: KM
authors.lastname: Saw
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Duska
authors.initials: D
authors.lastname: Separovic
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D002518:Ceramides / Q000494:pharmacology* / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D051379:Mice; D010088:Oxidoreductases / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D010778:Photochemotherapy; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D010088:Oxidoreductases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011412:Propanolamines; D011726:Pyridinium Compounds; D013110:Sphingosine; D000099157:Sphingosine Kinase; C560215:2-N-(16-(1'-pyridinium)hexadecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol; C527436:D-erythro-2-N-(160-(1''-pyridinium)hexadecanoyl)sphingosine bromide; C108138:dihydroceramide desaturase
keywords: Dihydroceramide desaturase; Photodynamic therapy; Sphingolipid analogs; Sphingosine kinase; Squamous cell carcinoma SCCVII
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