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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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Related in: MedlinePlus

Proliferation of MES-SA and MES-SA/DX5 cells over 7 days (D1–D7) after sonication.Ultrasound was applied at an intensity of 0.4 W/cm2 on D0 (arrow). Cells were counted immediately after sonication and plated at a density of 1×105 cells/dish. Data points are presented as mean ± SEM.
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pone-0048291-g002: Proliferation of MES-SA and MES-SA/DX5 cells over 7 days (D1–D7) after sonication.Ultrasound was applied at an intensity of 0.4 W/cm2 on D0 (arrow). Cells were counted immediately after sonication and plated at a density of 1×105 cells/dish. Data points are presented as mean ± SEM.

Mentions: According to the cell provider's online information sheet, the doubling time of MES-SA/DX5 is longer than that of MES-SA cells indicating that MDR cells proliferate at slower rate compared to the parent cells [29] (Figure 2 – significance difference was observed at D2 and D3). Despite this, the assessment of cell counts over a 7-days period (D1–D7) showed that the there was no difference in the growth ratios (calculated as: cell count at Dn/cell count at Dn-1, where n is the day (D) number) between untreated cells for the two cell phenotypes under our culture conditions (r2 = 0.93). The average maximum growth ratio/24 hr for untreated MES-SA and MES-SA/DX5 cells was 2.7±0.2 and 2.8±0.3, respectively. Sonication at 0.4 W/cm2 caused insignificant immediate cell lysis (<10%) based on immediate cell counting after sonication (D0). Both sonicated cell phenotypes proliferated at a lower but similar rate than untreated cells consistent with the data of Kamaev and Rapoport [20] (Figure 2). This similarity between both cell phenotypes after sonication implies either that the parent cells were far more affected by US irradiation –which is in contrast to the viability results - or that the resistant cells have undergone accelerated increase in cell numbers. The inspection of the growth ratios revealed that only the sonicated parent cells fluctuated in proliferation with a maximum growth ratio of 3.7±0.5 observed on the fourth day following US exposure (D4), whereas the sonicated resistant cells displayed a steadier increase in growth ratio that peaked also on D4 at a growth ratio of 3.0±0.2. Moreover, when the growth ratio at Day 1 (D1) was calculated taking into consideration only the viable portion of seeded cells (based on WST-8 assay), the calculated growth ratio (0.52±0.1) was in the range of the observed value (0.6±0.2) for the parent cells, whereas the resistant cell phenotype showed a large difference between the calculated and observed values (0.27±0.1 vs 0.7±0.1, respectively) reflecting a dramatic enhancement in cellular proliferation even at D1.


Ultrasound-induced new cellular mechanism involved in drug resistance.

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

Proliferation of MES-SA and MES-SA/DX5 cells over 7 days (D1–D7) after sonication.Ultrasound was applied at an intensity of 0.4 W/cm2 on D0 (arrow). Cells were counted immediately after sonication and plated at a density of 1×105 cells/dish. Data points are presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3526611&req=5

pone-0048291-g002: Proliferation of MES-SA and MES-SA/DX5 cells over 7 days (D1–D7) after sonication.Ultrasound was applied at an intensity of 0.4 W/cm2 on D0 (arrow). Cells were counted immediately after sonication and plated at a density of 1×105 cells/dish. Data points are presented as mean ± SEM.
Mentions: According to the cell provider's online information sheet, the doubling time of MES-SA/DX5 is longer than that of MES-SA cells indicating that MDR cells proliferate at slower rate compared to the parent cells [29] (Figure 2 – significance difference was observed at D2 and D3). Despite this, the assessment of cell counts over a 7-days period (D1–D7) showed that the there was no difference in the growth ratios (calculated as: cell count at Dn/cell count at Dn-1, where n is the day (D) number) between untreated cells for the two cell phenotypes under our culture conditions (r2 = 0.93). The average maximum growth ratio/24 hr for untreated MES-SA and MES-SA/DX5 cells was 2.7±0.2 and 2.8±0.3, respectively. Sonication at 0.4 W/cm2 caused insignificant immediate cell lysis (<10%) based on immediate cell counting after sonication (D0). Both sonicated cell phenotypes proliferated at a lower but similar rate than untreated cells consistent with the data of Kamaev and Rapoport [20] (Figure 2). This similarity between both cell phenotypes after sonication implies either that the parent cells were far more affected by US irradiation –which is in contrast to the viability results - or that the resistant cells have undergone accelerated increase in cell numbers. The inspection of the growth ratios revealed that only the sonicated parent cells fluctuated in proliferation with a maximum growth ratio of 3.7±0.5 observed on the fourth day following US exposure (D4), whereas the sonicated resistant cells displayed a steadier increase in growth ratio that peaked also on D4 at a growth ratio of 3.0±0.2. Moreover, when the growth ratio at Day 1 (D1) was calculated taking into consideration only the viable portion of seeded cells (based on WST-8 assay), the calculated growth ratio (0.52±0.1) was in the range of the observed value (0.6±0.2) for the parent cells, whereas the resistant cell phenotype showed a large difference between the calculated and observed values (0.27±0.1 vs 0.7±0.1, respectively) reflecting a dramatic enhancement in cellular proliferation even at D1.

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