Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment. Implications for endothelial apoptosis

Sabapathi Sathishkumar, Boris Boyanovsky, Alexander A. Karakashian, Krassimira Rozenova, Natalia V. Giltiay, Mahesh Kudrimoti, Mohammed Mohiuddin, Mansoor M. Ahmed, Mariana Nikolova-Karakashian

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101 Scopus citations

Abstract

Spatially fractionated high dose (grid) radiation treatment (SFGRT) involves irradiation of bulky tumors with one high, grid-delivered, dose of 15 Gy followed by multiple consecutive doses of 2 Gy each. The goal of this study is to determine the effect of this treatment on serum ceramide content and to investigate possible involvement of ceramide in tumor regression after SFGRT. Serum ceramide and Secretory SMase (S-SMase) were quantified in 11 patients before and at 24, 48 and 72 h after the dose of 15 Gy. Furthermore, LDL particles were isolated from the serum and their apoptotic ability was tested in human endothelial cells by TUNEL assay. Sixty seven per cent (6/8) of the patients with partial (PR) or complete (CR) response showed statistically significant increase in serum ceramide levels. Of the nonresponders in the study, none showed an elevation in ceramide. S-SMase activity underwent similar changes. LDL particles from serum of patients collected 72 hours after SFGRT sensitized the endothelial cells to undergo apoptosis in response to 5 Gy radiation that by itself had only modest effect on cell death. Independent elevation of ceramide content of endothelial cells that were otherwise resistant to radiation-induced cell death also was sufficient to sensitize these cells to apoptosis. Serum S-SMase activity and ceramide content increase following SFGRT and correlate with the clinical response. Apparently, these changes are in the LDL-associated ceramide and may contribute to better tumor reduction after SFGRT, due to the ability of LDL-derived ceramide to sensitize endothelial cells for apoptosis.

Original languageEnglish
Pages (from-to)979-986
Number of pages8
JournalCancer Biology and Therapy
Volume4
Issue number9
DOIs
StatePublished - Sep 2005

Bibliographical note

Funding Information:
This work was supported by the American Heart Association (Ohio Valley Affiliate) Grant-in-aid 0060312B to MNK and by the NIH grant RO1 AG019223 (to M.N.K.). We thank the Cardiovascular Research Group for invaluable help and advice.

Keywords

  • Apoptosis
  • Ceramide
  • Endothelial cells
  • Grid radiation
  • Serum and secretory sphingomyelinase

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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