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Ultrasound-induced new cellular mechanism involved in drug resistance.

Hassan MA, Furusawa Y, Minemura M, Rapoport N, Sugiyama T, Kondo T - PLoS ONE (2012)

Bottom Line: The acoustic effects in a biological milieu offer several scenarios for the reversal of multidrug resistance.In this study, we have observed higher sensitivity of doxorubicin-resistant uterine sarcoma MES-SA/DX5 cells to ultrasound exposure compared to its parent counterpart MES-SA cells; however, the results showed that the acoustic irradiation was genotoxic and could promote neotic division in exposed cells that was more pronounced in the resistant variant.Depending on the time and order of application of ultrasound and doxorubicin in combination treatments, there was either desensitization of the parent cells or sensitization of the resistant cells to doxorubicin action.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

ABSTRACT
The acoustic effects in a biological milieu offer several scenarios for the reversal of multidrug resistance. In this study, we have observed higher sensitivity of doxorubicin-resistant uterine sarcoma MES-SA/DX5 cells to ultrasound exposure compared to its parent counterpart MES-SA cells; however, the results showed that the acoustic irradiation was genotoxic and could promote neotic division in exposed cells that was more pronounced in the resistant variant. The neotic progeny, imaged microscopically 24 hr post sonication, could contribute in modulating the final cell survival when an apoptotic dose of doxorubicin was combined with ultrasound applied either simultaneously or sequentially in dual-treatment protocols. Depending on the time and order of application of ultrasound and doxorubicin in combination treatments, there was either desensitization of the parent cells or sensitization of the resistant cells to doxorubicin action.

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Fluorescent microscopy.Pictograms of MES-SA (a & b) and MES-SA/DX5 (c & d) cells 24 hr post sonication at 0.4 W/cm2. Cells were stained simultaneously with Hoechst 33342 and Alexa flour-488 – conjugated wheat germ agglutinin (WGA) in 2% paraformaldehyde (PFA)/PBS for 20 min followed by immediate observation. Cells show nuclear budding of genomic content (d) that is occasionally translocated through the cytoplasm (b) and emerges to form a small cell (Raju cell) (a). Two distinct forms of nuclear budding can be identified in treated MES-SA cells bearing similarity to neotic cytokinesis described by Rajaraman et al. [33], namely, (a) sequential cytokinesis type-2 perinuclear and (b) sequential cytokinesis type-1 pericellular, whereas the first form only was observed in treated MES-SA/DX5 cells. Open-head arrows indicate nuclear budding; closed-head arrows indicate the surrounding membranes of emerging cells. (e & f) Sonicated MES-SA cells showing multiple cytokinesis captured at the fourth (D4) and fifth (D5) days post exposure, respectively. (g) Control MES-SA cell with spontaneous cytokinesis. Cells (e–g) resemble in morphology neotic mother cells shown by Sundaram et al. [31]. Bars, 10 µm.
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pone-0048291-g003: Fluorescent microscopy.Pictograms of MES-SA (a & b) and MES-SA/DX5 (c & d) cells 24 hr post sonication at 0.4 W/cm2. Cells were stained simultaneously with Hoechst 33342 and Alexa flour-488 – conjugated wheat germ agglutinin (WGA) in 2% paraformaldehyde (PFA)/PBS for 20 min followed by immediate observation. Cells show nuclear budding of genomic content (d) that is occasionally translocated through the cytoplasm (b) and emerges to form a small cell (Raju cell) (a). Two distinct forms of nuclear budding can be identified in treated MES-SA cells bearing similarity to neotic cytokinesis described by Rajaraman et al. [33], namely, (a) sequential cytokinesis type-2 perinuclear and (b) sequential cytokinesis type-1 pericellular, whereas the first form only was observed in treated MES-SA/DX5 cells. Open-head arrows indicate nuclear budding; closed-head arrows indicate the surrounding membranes of emerging cells. (e & f) Sonicated MES-SA cells showing multiple cytokinesis captured at the fourth (D4) and fifth (D5) days post exposure, respectively. (g) Control MES-SA cell with spontaneous cytokinesis. Cells (e–g) resemble in morphology neotic mother cells shown by Sundaram et al. [31]. Bars, 10 µm.

Mentions: The microscopic examination of cells 24 hr after sonication at 0.4 W/m2 revealed the presence of different morphological features that can be approximately fitted to those reported recently in reference [30]. However, double staining of adherent cells with Hoechst 33342 and WGA showed the emergence of nuclear buds that were sometimes seen during translocation toward the cell membrane (Figure 3). Although the emergence of these buds occurred more frequently in sonicated MES-SA/DX5 cells, it was also observed in sonicated MES-SA cells, but at lesser frequency and in two distinct forms of emergence as shown in Figure 3 a & b. Some sonicated MES-SA cells captured four or five days post sonication showed morphological features similar to those reported by Sundaram et al. in a number of irradiated mouse- and human- derived cancers [31] (Figure 3 e & f). In some occasions, one or two similar cells were also observed in normal culture dishes indicating the spontaneity of the phenomenon (Figure 3 g).


Ultrasound-induced new cellular mechanism involved in drug resistance.

Hassan MA, Furusawa Y, Minemura M, Rapoport N, Sugiyama T, Kondo T - PLoS ONE (2012)

Fluorescent microscopy.Pictograms of MES-SA (a & b) and MES-SA/DX5 (c & d) cells 24 hr post sonication at 0.4 W/cm2. Cells were stained simultaneously with Hoechst 33342 and Alexa flour-488 – conjugated wheat germ agglutinin (WGA) in 2% paraformaldehyde (PFA)/PBS for 20 min followed by immediate observation. Cells show nuclear budding of genomic content (d) that is occasionally translocated through the cytoplasm (b) and emerges to form a small cell (Raju cell) (a). Two distinct forms of nuclear budding can be identified in treated MES-SA cells bearing similarity to neotic cytokinesis described by Rajaraman et al. [33], namely, (a) sequential cytokinesis type-2 perinuclear and (b) sequential cytokinesis type-1 pericellular, whereas the first form only was observed in treated MES-SA/DX5 cells. Open-head arrows indicate nuclear budding; closed-head arrows indicate the surrounding membranes of emerging cells. (e & f) Sonicated MES-SA cells showing multiple cytokinesis captured at the fourth (D4) and fifth (D5) days post exposure, respectively. (g) Control MES-SA cell with spontaneous cytokinesis. Cells (e–g) resemble in morphology neotic mother cells shown by Sundaram et al. [31]. Bars, 10 µm.
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pone-0048291-g003: Fluorescent microscopy.Pictograms of MES-SA (a & b) and MES-SA/DX5 (c & d) cells 24 hr post sonication at 0.4 W/cm2. Cells were stained simultaneously with Hoechst 33342 and Alexa flour-488 – conjugated wheat germ agglutinin (WGA) in 2% paraformaldehyde (PFA)/PBS for 20 min followed by immediate observation. Cells show nuclear budding of genomic content (d) that is occasionally translocated through the cytoplasm (b) and emerges to form a small cell (Raju cell) (a). Two distinct forms of nuclear budding can be identified in treated MES-SA cells bearing similarity to neotic cytokinesis described by Rajaraman et al. [33], namely, (a) sequential cytokinesis type-2 perinuclear and (b) sequential cytokinesis type-1 pericellular, whereas the first form only was observed in treated MES-SA/DX5 cells. Open-head arrows indicate nuclear budding; closed-head arrows indicate the surrounding membranes of emerging cells. (e & f) Sonicated MES-SA cells showing multiple cytokinesis captured at the fourth (D4) and fifth (D5) days post exposure, respectively. (g) Control MES-SA cell with spontaneous cytokinesis. Cells (e–g) resemble in morphology neotic mother cells shown by Sundaram et al. [31]. Bars, 10 µm.
Mentions: The microscopic examination of cells 24 hr after sonication at 0.4 W/m2 revealed the presence of different morphological features that can be approximately fitted to those reported recently in reference [30]. However, double staining of adherent cells with Hoechst 33342 and WGA showed the emergence of nuclear buds that were sometimes seen during translocation toward the cell membrane (Figure 3). Although the emergence of these buds occurred more frequently in sonicated MES-SA/DX5 cells, it was also observed in sonicated MES-SA cells, but at lesser frequency and in two distinct forms of emergence as shown in Figure 3 a & b. Some sonicated MES-SA cells captured four or five days post sonication showed morphological features similar to those reported by Sundaram et al. in a number of irradiated mouse- and human- derived cancers [31] (Figure 3 e & f). In some occasions, one or two similar cells were also observed in normal culture dishes indicating the spontaneity of the phenomenon (Figure 3 g).

Bottom Line: The acoustic effects in a biological milieu offer several scenarios for the reversal of multidrug resistance.In this study, we have observed higher sensitivity of doxorubicin-resistant uterine sarcoma MES-SA/DX5 cells to ultrasound exposure compared to its parent counterpart MES-SA cells; however, the results showed that the acoustic irradiation was genotoxic and could promote neotic division in exposed cells that was more pronounced in the resistant variant.Depending on the time and order of application of ultrasound and doxorubicin in combination treatments, there was either desensitization of the parent cells or sensitization of the resistant cells to doxorubicin action.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

ABSTRACT
The acoustic effects in a biological milieu offer several scenarios for the reversal of multidrug resistance. In this study, we have observed higher sensitivity of doxorubicin-resistant uterine sarcoma MES-SA/DX5 cells to ultrasound exposure compared to its parent counterpart MES-SA cells; however, the results showed that the acoustic irradiation was genotoxic and could promote neotic division in exposed cells that was more pronounced in the resistant variant. The neotic progeny, imaged microscopically 24 hr post sonication, could contribute in modulating the final cell survival when an apoptotic dose of doxorubicin was combined with ultrasound applied either simultaneously or sequentially in dual-treatment protocols. Depending on the time and order of application of ultrasound and doxorubicin in combination treatments, there was either desensitization of the parent cells or sensitization of the resistant cells to doxorubicin action.

Show MeSH
Related in: MedlinePlus