TY - JOUR
T1 - A photodynamic pathway to apoptosis and necrosis induced by dimethyl tetrahydroxyhelianthrone and hypericin in leukaemic cells
T2 - Possible relevance to photodynamic therapy
AU - Lavie, G.
AU - Kaplinsky, C.
AU - Toren, A.
AU - Aizman, I.
AU - Meruelo, D.
AU - Mazur, Y.
AU - Mandel, M.
N1 - Funding Information:
The authors are grateful to Dr Joseph Lotem, Department of Molecular Genetics, The Weizmann Institute of Science, Israel, for a critical review of this manuscript. The study was supported by NIH grant no. HL 53379-01 and by grant no. 3181 of the Israeli Health Ministr y .
PY - 1999
Y1 - 1999
N2 - The mechanism of cell death induction by dimethyl tetrahydroxyhelianthrone (DTHe), a new second-generation photodynamic sensitizer, is analysed in human leukaemic cell lines in comparison with the structurally related hypericin. DTHe has a broad range of light spectrum absorption that enables effective utilization of polychromatic light. Photosensitization of HL-60 cells with low doses of DTHe (0.65 μM DTHe and 7.2 J cm-2 light energy) induced rapid apoptosis of ≥ 90% of the cells. At doses ≥ 2 μM, dying cells assumed morphological necrosis with perinucleolar condensation of chromatin in HL-60 and K-562 cell lines. Although nuclear fragmentation that is characteristic to apoptosis was prevented, DNA digestion to oligonucleosomes proceeded unhindered. Such incomplete apoptosis was more prevalent with the related analogue hypericin throughout most doses of photosensitization. Despite hypericin being a stronger photosensitizer, DTHe exhibited advantageous phototoxic properties to tumour cells, initiating apoptosis at concentrations about threefold lower than hypericin. Photosensitization of the cells induced dissociation of the nuclear envelope, releasing lamins into the cytosol. DTHe also differed from hypericin in effects exerted on the nuclear lamina, causing release of an 86-kDa lamin protein into the cytosol that was unique to DTHe. Within the nucleus, nuclear envelope lamin B underwent covalent polymerization, which did not affect apoptotic nuclear fragmentation at low doses of DTHe. At higher doses, polymerization may have been extensive enough to prevent nuclear collapse. Hut-78, CD4+ cells were resistant to the photodynamically activated apoptotic pathway. Beyond the tolerated levels of photodynamic damage, these cells died exclusively via necrosis. Hut-78 cells overexpress Bcl-X(L) as well as a truncated Bcl-X(L)(tr) isoform that could contribute to the observed resistance to apoptosis.
AB - The mechanism of cell death induction by dimethyl tetrahydroxyhelianthrone (DTHe), a new second-generation photodynamic sensitizer, is analysed in human leukaemic cell lines in comparison with the structurally related hypericin. DTHe has a broad range of light spectrum absorption that enables effective utilization of polychromatic light. Photosensitization of HL-60 cells with low doses of DTHe (0.65 μM DTHe and 7.2 J cm-2 light energy) induced rapid apoptosis of ≥ 90% of the cells. At doses ≥ 2 μM, dying cells assumed morphological necrosis with perinucleolar condensation of chromatin in HL-60 and K-562 cell lines. Although nuclear fragmentation that is characteristic to apoptosis was prevented, DNA digestion to oligonucleosomes proceeded unhindered. Such incomplete apoptosis was more prevalent with the related analogue hypericin throughout most doses of photosensitization. Despite hypericin being a stronger photosensitizer, DTHe exhibited advantageous phototoxic properties to tumour cells, initiating apoptosis at concentrations about threefold lower than hypericin. Photosensitization of the cells induced dissociation of the nuclear envelope, releasing lamins into the cytosol. DTHe also differed from hypericin in effects exerted on the nuclear lamina, causing release of an 86-kDa lamin protein into the cytosol that was unique to DTHe. Within the nucleus, nuclear envelope lamin B underwent covalent polymerization, which did not affect apoptotic nuclear fragmentation at low doses of DTHe. At higher doses, polymerization may have been extensive enough to prevent nuclear collapse. Hut-78, CD4+ cells were resistant to the photodynamically activated apoptotic pathway. Beyond the tolerated levels of photodynamic damage, these cells died exclusively via necrosis. Hut-78 cells overexpress Bcl-X(L) as well as a truncated Bcl-X(L)(tr) isoform that could contribute to the observed resistance to apoptosis.
KW - Apoptosis
KW - Bax
KW - Bcl-X
KW - Dimethyl tetrahydroxyhelianthrone
KW - Hypericin
KW - Lamin
KW - Photodynamic therapy
UR - http://www.scopus.com/inward/record.url?scp=0032928325&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6690066
DO - 10.1038/sj.bjc.6690066
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C2 - 10027308
AN - SCOPUS:0032928325
SN - 0007-0920
VL - 79
SP - 423
EP - 432
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 3-4
ER -
