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C16-Ceramide Analog Combined with Pc 4 Photodynamic Therapy Evokes Enhanced Total Ceramide Accumulation, Promotion of DEVDase Activation in the Absence of Apoptosis, and Augmented Overall Cell Killing.

Separovic D, Saad ZH, Edwin EA, Bielawski J, Pierce JS, Buren EV, Bielawska A - J Lipids (2010)

Bottom Line: Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30) was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels.Notably, treatment with the combination resulted in augmented overall cell killing.Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.

ABSTRACT
Because of the failure of single modality approaches, combination therapy for cancer treatment is a promising alternative. Sphingolipid analogs, with or without anticancer drugs, can improve tumor response. C16-pyridinium ceramide analog LCL30, was used in combination with photodynamic therapy (PDT), an anticancer treatment modality, to test the hypothesis that the combined treatment will trigger changes in the sphingolipid profile and promote cell death. Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30) was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels. Unlike LCL30, PDT, alone or combined, increased total dihydroceramide levels. Sphingosine levels were unaffected by LCL30, but were abolished after PDT or the combination. LCL30-triggered rise in sphingosine-1-phosphate was reversed post-PDT or the combination. DEVDase activation was evoked after PDT or LCL30, and was promoted post- PDT/LCL30. Neither mitochondrial depolarization nor apoptosis were observed after any of the treatments. Notably, treatment with the combination resulted in augmented overall cell killing. Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.

No MeSH data available.


Related in: MedlinePlus

De novo ceramide metabolism.
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Related In: Results  -  Collection


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fig1: De novo ceramide metabolism.

Mentions: Here, we used for the first time LCL30 in combination with PDT to determine their effects on endogenous SLs, apoptosis, and clonogenic survival in SCCVII mouse squamous carcinoma cells (SCCVII cells). The model was chosen in order to use the results of this study in our future in vivo work in syngeneic mouse SCCVII squamous carcinomas, a recognized mouse model for human head and neck cancers [22], since intact immune system is a key to PDT therapeutic success [16, 17]. For PDT, silicon phthalocyanine Pc 4, a photosensitizer with physicochemical properties superior to Photofrin [23, 24], was chosen for these investigations. SLs that were analyzed by mass spectrometry (MS) are shown in Figure 1 as part of, or relative to the de novo ceramide pathway. Others [25–30] and we [21, 31–35] have shown that the de novo ceramide pathway modulates response to anticancer drugs, including PDT. For example, we have shown in Jurkat cells that silencing of ceramide-utilizing enzyme sphingomyelin synthase leads to enhanced ceramide and dihydroceramide accumulation with concomitant promotion of apoptosis [32]. Combining PDT with the anticancer LCL30 is expected to promote tumor response to PDT and, therefore, improve clinical PDT.


C16-Ceramide Analog Combined with Pc 4 Photodynamic Therapy Evokes Enhanced Total Ceramide Accumulation, Promotion of DEVDase Activation in the Absence of Apoptosis, and Augmented Overall Cell Killing.

Separovic D, Saad ZH, Edwin EA, Bielawski J, Pierce JS, Buren EV, Bielawska A - J Lipids (2010)

De novo ceramide metabolism.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066794&req=5

fig1: De novo ceramide metabolism.
Mentions: Here, we used for the first time LCL30 in combination with PDT to determine their effects on endogenous SLs, apoptosis, and clonogenic survival in SCCVII mouse squamous carcinoma cells (SCCVII cells). The model was chosen in order to use the results of this study in our future in vivo work in syngeneic mouse SCCVII squamous carcinomas, a recognized mouse model for human head and neck cancers [22], since intact immune system is a key to PDT therapeutic success [16, 17]. For PDT, silicon phthalocyanine Pc 4, a photosensitizer with physicochemical properties superior to Photofrin [23, 24], was chosen for these investigations. SLs that were analyzed by mass spectrometry (MS) are shown in Figure 1 as part of, or relative to the de novo ceramide pathway. Others [25–30] and we [21, 31–35] have shown that the de novo ceramide pathway modulates response to anticancer drugs, including PDT. For example, we have shown in Jurkat cells that silencing of ceramide-utilizing enzyme sphingomyelin synthase leads to enhanced ceramide and dihydroceramide accumulation with concomitant promotion of apoptosis [32]. Combining PDT with the anticancer LCL30 is expected to promote tumor response to PDT and, therefore, improve clinical PDT.

Bottom Line: Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30) was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels.Notably, treatment with the combination resulted in augmented overall cell killing.Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.

ABSTRACT
Because of the failure of single modality approaches, combination therapy for cancer treatment is a promising alternative. Sphingolipid analogs, with or without anticancer drugs, can improve tumor response. C16-pyridinium ceramide analog LCL30, was used in combination with photodynamic therapy (PDT), an anticancer treatment modality, to test the hypothesis that the combined treatment will trigger changes in the sphingolipid profile and promote cell death. Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30) was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels. Unlike LCL30, PDT, alone or combined, increased total dihydroceramide levels. Sphingosine levels were unaffected by LCL30, but were abolished after PDT or the combination. LCL30-triggered rise in sphingosine-1-phosphate was reversed post-PDT or the combination. DEVDase activation was evoked after PDT or LCL30, and was promoted post- PDT/LCL30. Neither mitochondrial depolarization nor apoptosis were observed after any of the treatments. Notably, treatment with the combination resulted in augmented overall cell killing. Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.

No MeSH data available.


Related in: MedlinePlus