Detection and quantification of the evolution dynamics of apoptosis using the PET voltage sensor18F-fluorobenzyl triphenyl phosphonium

Igal Madar, Yi Huang, Hayden Ravert, Susan L. Dalrymple, Nancy E. Davidson, John Tod Isaacs, Robert F Dannals, J. James Frost

Research output: Contribution to journalArticle

Abstract

Apoptosis is a key mechanism in numerous pathologies.However, there are no effective noninvasive means available for an early detection and quantitative assessment of evolution dynamics of the apoptotic process. Here, we have characterized the ability of the novel PET voltage sensor 18F- fluorobenzyl triphenyl phosphonium (18F-FBnTP) to quantify the time-dependent apoptotic action of the taxanespaclitaxel and docetaxel in vitro and in vivo.Methods: The duration-dependent treatment effect of paclitaxel on 18F-FBnTP uptake was assayed in human MDA-MB-231 breast carcinoma cells. The expression of the proapoptotic Bax and antiapoptotic Bcl-2mitochondrial proteins, release of the apoptogen cytochrome c, and activation of executioner caspase-3 were determined by Western blotting. The fraction of viable cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide. The effect of docetaxel on 18F-FBnTP and 18F-FDG uptake in orthotopic prostate tumors inmicewas compared. Results: 18F-FBnTP cellular uptake in viable cells declined linearly with the increasing duration of paclitaxel treatment, from 3 to 24 h, and plateaued at 48 h. The extent of decrease of 18F-FBnTP correlated strongly with the Bax-to-Bcl-2 ratio (R2 = 0.83) and release of cytochrome c (R2 = 0.92), but preceded in time the caspase-3 cleavage. The P-glycoprotein blocker verapamil did not interfere with 18F-FBnTP cellular uptake. 18F-FBnTP prostate tumor contrast was greater than 18F-FDG prostate tumor contrast. Docetaxel caused a marked decrease (52.4%) of 18F-FBnTP tumor uptake, within 48 h, whereas 18F-FDG was much less affected (12%). Conclusion: The voltage sensor 18F-FBnTP is a viable means for quantification of paclitaxel pharmacodynamics. 18F-FBnTP permits the detection of paclitaxel apoptotic action in vivo earlier than does 18F-FDG. 18F-FBnTP may afford a novel approach for early detection and quantitative assessment of the cumulative-effect kinetics of proapoptotic drugs and conditions using PET.

Original languageEnglish (US)
Pages (from-to)774-780
Number of pages7
JournalJournal of Nuclear Medicine
Volume50
Issue number5
DOIs
Publication statusPublished - May 1 2009

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Keywords

  • F-fluorobenzyl triphenyl phosphonium
  • Apoptosis
  • Breast carcinoma cell line
  • Molecular biology
  • Molecular imaging
  • PET
  • Taxanes

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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