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Apoptosis Induction of Human Myeloid Leukemic Cells by Ultrasound Exposure¹

Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel [H. A., L. A. R., M. B., M. B-S., D. A., J. R.]; Department of Molecular Cell Biology, Weizmann Institute of Sciences, Rehovot, Israel [D. Z.]; and Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel [U. R.]

Therapeutic ultrasound (ULS) and the resulting cavitation process has been shown to induce irreversible cell damage. In this study, we wanted to further investigate the mechanism of ULS-induced cell death and to determine whether apoptosis is involved. High intensity focused pulsed ULS sonication at a frequency of 750 KHz was delivered to HL-60, K562, U937, and M1/2 leukemia cell line cultures. ULS exposure used with induction of transient cavitation in the focal area was delivered with an intensity level of 103.7 W/cm² and 54.6 W/cm² spatial-peak temporal-average intensity. As a control, ULS of lower intensity was delivered at 22.4 W/cm² spatial-peak temporal-average intensity, presumably without generation of cavitation. Our results indicated that DNA damage induced by ULS cavitation did not involve generation of free radicals in the culture media. Morphological alterations observed in cells after exposure to ULS included: cell shrinkage, membrane blebbing, chromatin condensation, nuclear fragmentation, and apoptotic body formation. Apoptotic cells were evaluated by fluorescence microscopy and detected using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, which identifies DNA breaks, and by the leakage of phosphatidylserine from the inner to the outer side of the membrane layer of treated cells. Some bioeffects induced on sonicated HL-60 cells, such as inhibition of cell proliferation, DNA repair, and cell-dependent apoptosis, were found to be similar to those produced by -irradiation. Thus, much of the cell damage induced by therapeutic ULS in leukemia cells surviving ULS exposure appears to occur through an apoptotic mechanism.

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