title: Preferential enlargement of leukemia cells using cytoskeletal-directed agents and cell cycle growth control parameters to induce sensitivity to low frequency ultrasound.
abstract: Sonodynamic therapy (SDT) is a form of ultrasound therapy that has been shown to preferentially damage malignant cells based on the relatively enlarged size and altered cytology of neoplastic cells in comparison to normal cells. This study sought to determine whether cytoskeletal-directed agents that either disrupt (cytochalasin B and vincristine) or rigidify (jasplakinolide and paclitaxel) microfilaments and microtubules, respectively, affect ultrasonic sensitivity. U937 human monocytic leukemia cell populations were treated with each cytoskeletal-directed agent alone, and then sonicated at 23.5 kHz under relatively low power and intensity (20-40 W; 10-20 W/cm(2)), or at 20 kHz using moderate power and intensity (60 W; 80 W/cm(2)). In addition, human leukemia lines U937, THP1, K562, and Molt-4, and the murine leukemia line L1210 were sonicated using pulsed 20 kHz ultrasound (80.6 W; 107.5 W/cm(2)) both with and without the addition of cytoskeletal-directed agents to assess whether cytoskeletal-directed agents can potentiate ultrasonic sensitivity in different leukemia lines. Human hematopoietic stem cells (hHSCs) and leukocytes were sonicated with continuous 23.5 kHz ultrasound (20 W; 10 W/cm(2)) to determine whether this approach elicited the preferential damage of neoplastic cells over normal blood components. To determine whether ultrasonic sensitivity is exclusively dependent on cell size, leukemia cells were also enlarged via alteration of cell growth parameters including serum deprivation and re-addition, and plateau-phase subculturing. Results indicated that cytochalasin B/ultrasound treatments had the highest rates of initial U937 cell damage. The cells enlarged and partially synchronized, either by serum deprivation and re-addition or by plateau-phase subculturing and synchronous release, were not comparably sensitive to ultrasonic destruction based solely on their cell size. In addition, cytochalasin B significantly potentiated the ultrasonic sensitivity of all neoplastic cell lines, but not in normal blood cells, suggesting that preferential damage is attainable with this treatment protocol. Therefore, it is likely that ultrasonic cell lysis depends not only on cell size and type, but also on the specific molecular mechanisms used to induce cell enlargement and their effects on cell integrity. This is supported by the fact that either the microfilament-or microtubule-disrupting agent produced a higher rate of lysis for cells of a given size than the corresponding stabilizing agents.
authors: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY 13244, USA. Electronic address: mrtrendo@syr.edu.
authors: Matthew
authors: M
authors: Trendowski
authors: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY 13244, USA.
authors: Victoria
authors: V
authors: Wong
authors: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY 13244, USA.
authors: Joseph N
authors: JN
authors: Zoino
authors: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY 13244, USA.
authors: Timothy D
authors: TD
authors: Christen
authors: School of Dental Medicine, Tufts University, 1 Kneeland Street, Boston, MA 02111, USA.
authors: Lauren
authors: L
authors: Gadeberg
authors: Family Medicine Center and Residency, Eastern Maine Medical Center, 895 Union Street, Suite 12, Bangor, ME 04401, USA.
authors: Michelle
authors: M
authors: Sansky
authors: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY 13244, USA.
authors: Thomas P
authors: TP
authors: Fondy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000502:physiology; D016895:Culture Media, Serum-Free; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D007939:Leukemia L1210 / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D020298:U937 Cells; D014464:Ultrasonic Therapy; D014463:Ultrasonography; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D047630:Depsipeptides; C057531:jasplakinolide; D003571:Cytochalasin B; D014750:Vincristine; D017239:Paclitaxel
keywords: Cell-cycle synchronization; Chemotherapy; Cytoskeletal-directed agents; Leukemia; Sonodynamic therapy; Ultrasound