TY - JOUR
T1 - Niemann-Pick human lymphoblasts are resistant to phthalocyanine 4-photodynamic therapy-induced apoptosis
AU - Separovic, Duska
AU - Pink, John J.
AU - Oleinick, Nancy A.
AU - Kester, Mark
AU - Boothman, David A.
AU - McLoughlin, Maureen
AU - Peña, Louis A.
AU - Haimovitz-Friedman, Adriana
N1 - Funding Information:
The authors are indebted to Drs. Malcolm E. Kenney and Ying-syi Li (Dept. Chemistry, CWRU) for the generous gift of [14C] Pc 4. This research was supported by U.S. Public Health Service Grants P01 CA48735 to N.L.O., R29CA77475 to D.S., and Cancer Center Support Grant P30 CA43703 from the National Cancer Institute, DHHS. Funding was also supplied by U.S. Army Material Command DOD Grant BC97143 to D.A.B. and a post-doctoral fellowship to J.J.P.
PY - 1999/5/19
Y1 - 1999/5/19
N2 - Stress-induced activation of sphingomyelinase (SMase) leading to generation of ceramide, a lipid mediator, has been associated with apoptosis in several malignant and nonmalignant cell lines. Photodynamic therapy (PDT), with the phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)2(CH2)3N(CH3)2], is an oxidative stress associated with increased ceramide generation and subsequent induction of apoptosis in various cell types. We assessed the role of SMase in photocytotoxicity. Normal human lymphoblasts accumulated ceramide and underwent apoptosis after Pc 4-PDT. In contrast, Niemann-Pick disease (NPD) lymphoblasts, which are deficient in acid sphingomyelinase (ASMase) activity, failed to respond to Pc 4-PDT with ceramide accumulation and apoptosis, suggesting that ASMase may be a Pc 4-PDT target. NPD lymphoblasts were exposed to exogenous bacterial sphingomyelinase (bSMase) to test whether these defects are reversible. Treatment of NPD cells with bSMase itself led to elevated ceramide formation, which did not translate into induction of apoptosis. However, a combination of Pc 4-PDT + bSMase induced a significant apoptotic response. Thus, the combined treatment of Pc 4-PDT + bSMase, rather than bSMase alone, was required to restore apoptosis in NPD cells. These data support the hypothesis that SMase is a proapoptotic factor determining responsiveness of cells to Pc 4-PDT.
AB - Stress-induced activation of sphingomyelinase (SMase) leading to generation of ceramide, a lipid mediator, has been associated with apoptosis in several malignant and nonmalignant cell lines. Photodynamic therapy (PDT), with the phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)2(CH2)3N(CH3)2], is an oxidative stress associated with increased ceramide generation and subsequent induction of apoptosis in various cell types. We assessed the role of SMase in photocytotoxicity. Normal human lymphoblasts accumulated ceramide and underwent apoptosis after Pc 4-PDT. In contrast, Niemann-Pick disease (NPD) lymphoblasts, which are deficient in acid sphingomyelinase (ASMase) activity, failed to respond to Pc 4-PDT with ceramide accumulation and apoptosis, suggesting that ASMase may be a Pc 4-PDT target. NPD lymphoblasts were exposed to exogenous bacterial sphingomyelinase (bSMase) to test whether these defects are reversible. Treatment of NPD cells with bSMase itself led to elevated ceramide formation, which did not translate into induction of apoptosis. However, a combination of Pc 4-PDT + bSMase induced a significant apoptotic response. Thus, the combined treatment of Pc 4-PDT + bSMase, rather than bSMase alone, was required to restore apoptosis in NPD cells. These data support the hypothesis that SMase is a proapoptotic factor determining responsiveness of cells to Pc 4-PDT.
KW - Acid sphingomyelinase
KW - Apoptosis
KW - Ceramide
KW - Pc 4
KW - Phthalocyanine
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U2 - 10.1006/bbrc.1999.0670
DO - 10.1006/bbrc.1999.0670
M3 - Article
C2 - 10329416
AN - SCOPUS:0033583789
SN - 0006-291X
VL - 258
SP - 506
EP - 512
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -