title: Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy-generated vaccine.
abstract: Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 µM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill.
authors.affiliation: Integrative Oncology Department, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Mladen
authors.initials: M
authors.lastname: Korbelik
authors.affiliation: Integrative Oncology Department, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Judit
authors.initials: J
authors.lastname: Banáth
authors.affiliation: Integrative Oncology Department, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Integrative Oncology Department, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Kyi Min
authors.initials: KM
authors.lastname: Saw
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Duska
authors.initials: D
authors.lastname: Separovic
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors*; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D056747:Immunomodulation; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D010778:Photochemotherapy; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D055573:Acid Ceramidase
keywords: acid ceramidase inhibitor LCL521; immunoregulatory cells; photodynamic therapy; photodynamic therapy-generated cancer vaccine