The long-term objective of our research is to augment the efficacy of the cancer treatment photodynamic therapy (PDT). In PDT, utilizing a photosensitizer, visible light, and oxygen, reactive oxygen species are generated in a cellular target that can result in apoptotic cell death. PDT induces the de novo production of creamed, a sphingolipid that contributes importantly to apoptosis. The underlying mechanisms of de novo ceramide generation during PDT apoptosis remain obscure. This poses an important problem; because without the complete understanding of how ceramide generation occurs, it is highly improbable that ceramide can be manipulated to advance PDT cytotoxic potential. The objective of this application is to determine the regulation of ceramide production and the role of ceramide-metabolizing enzymes in apoptosis after PDT. The central hypothesis is: PDT-induced de novo ceramide production is controlled via oxidative stress dependent ceramide metabolizing enzymes and promotes apoptosis.
Two specific aims will test the hypothesis; (1) identify the enzymes involved in regulating de novo synthesis of ceramide during PDT. Sphingomyelin synthase and glucosylceramide synthase will be characterized as potential PDT molecular targets. (2) Determine the influence of oxidative stress on de novo ceramide production and apoptosis after PDT. Specifically, the role of superoxide dismutase-dependent superoxide in these processes will be investigated. To address the aims, cells overexpressing sphingomyelin synthase, glucosylceramide synthase and superoxide dismutases, respectively, will be generated. In addition, glucosylceramide synthase-null mouse melanoma cells and embryonic fibroblasts isolated from Mn superoxide dismutase-knockout mice will be used. The impact of the proposed work is that it is expected to lead to strategies that will selectively block enzymes that utilize ceramide to potentiate cellular ceramide levels and ultimately promote PDT efficiency.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077475-07
Application #
7029648
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Wong, Rosemary S
Project Start
1998-12-02
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
7
Fiscal Year
2006
Total Cost
$232,973
Indirect Cost
Name
Wayne State University
Department
Public Health & Prev Medicine
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Boppana, Nithin B; DeLor, Jeremy S; Van Buren, Eric et al. (2016) Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway. J Photochem Photobiol B 159:191-5
Korbelik, Mladen; Hamblin, Michael R (2015) The impact of macrophage-cancer cell interaction on the efficacy of photodynamic therapy. Photochem Photobiol Sci 14:1403-9
Boppana, Nithin B; Stochaj, Ursula; Kodiha, Mohamed et al. (2015) Enhanced killing of SCC17B human head and neck squamous cell carcinoma cells after photodynamic therapy plus fenretinide via the de novo sphingolipid biosynthesis pathway and apoptosis. Int J Oncol 46:2003-10
Boppana, Nithin B; Stochaj, Ursula; Kodiha, Mohamed et al. (2015) C6-pyridinium ceramide sensitizes SCC17B human head and neck squamous cell carcinoma cells to photodynamic therapy. J Photochem Photobiol B 143:163-8
Boppana, Nithin B; Kodiha, Mohamed; Stochaj, Ursula et al. (2014) Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization. Photochem Photobiol Sci 13:1621-7
Korbelik, Mladen; BanĂ¡th, Judit; Sun, Jinghai et al. (2014) Ceramide and sphingosine-1-phosphate act as photodynamic therapy-elicited damage-associated molecular patterns: cell surface exposure. Int Immunopharmacol 20:359-65
Breen, Paul; Joseph, Nicholas; Thompson, Kyle et al. (2013) Dihydroceramide desaturase knockdown impacts sphingolipids and apoptosis after photodamage in human head and neck squamous carcinoma cells. Anticancer Res 33:77-84
Separovic, Duska; Breen, Paul; Boppana, Nithin B et al. (2013) Increased killing of SCCVII squamous cell carcinoma cells after the combination of Pc 4 photodynamic therapy and dasatinib is associated with enhanced caspase-3 activity and ceramide synthase 1 upregulation. Int J Oncol 43:2064-72
Korbelik, Mladen; Zhang, Wei; Saw, Kyi Min et al. (2013) Cationic ceramides and analogues, LCL30 and LCL85, as adjuvants to photodynamic therapy of tumors. J Photochem Photobiol B 126:72-7
Separovic, Duska; Breen, Paul; Joseph, Nicholas et al. (2012) siRNA-mediated down-regulation of ceramide synthase 1 leads to apoptotic resistance in human head and neck squamous carcinoma cells after photodynamic therapy. Anticancer Res 32:2479-2485

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