Low-intensity ultrasound adjuvant therapy: Enhancement of doxorubicin-induced cytotoxicity and the acoustic mechanisms involved

Takashi Kondo, Toru Yoshida, Ryohei Ogawa, Mariame A. Hassan, Yukihiro Furusawa, Qing Li Zhao, Akihiko Watanabe, Akihiro Morii, Loreto B. Feril, Katsuro Tachibana, Hiroshi Kitagawa, Yoshiaki Tabuchi, Ichiro Takasaki, Mohammad H. Shehata, Nobuki Kudo, Kazuhiro Tsukada

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: In this study, the effects of low-intensity pulsed ultrasound (LIU) as an adjuvant to doxorubicin (DOX) treatment was further investigated in comparison to hyperthermia as another widely used adjuvant. The effects were compared with respect to cell killing and apoptosis induction in U937 cells. Human primary liver cancer (PLC) cells were also used to evaluate the effects of the combinations. The use of an echo contrast agent was investigated for further enhancement of cytotoxicity. Finally, the acoustic mechanisms involved were investigated. Methods: The effects of different treatment regimens on cell viability were determined using the Trypan blue dye-exclusion test. Apoptosis induction was detected by flow cytometry using fluorescein isothiocyanate- annexin V and propidium iodide staining. The mechanistic study involved electron paramagnetic spin trapping for detecting free radical formation as an indicator of the occurrence of inertial cavitation and spectrophotometry for sucrose hydrolysis as an indicator for noncavitational effects. Results: The combination treatments exerted synergistic effects on cytotoxicity depending on the acoustic conditions used. The use of LIU as an adjuvant to DOX treatment was shown to be superior to the use of hyperthermia as an adjuvant. Moreover, the combination seems to be promising for other cancer types provided that the acoustic conditions are properly selected with respect to drug concentration. The key ultrasound mechanism responsible for the synergism observed was shown to be the production of free radicals by inertial cavitation. Non-cavitational forces were also shown to contribute to the effect. Conclusion: This study is motivating to engage in in vivo research with various cancer types as a step toward clinical applicability and is emphasizing on the importance of developing therapeutic protocols for setting LIU parameters with respect to other therapeutic conditions.

Original languageEnglish
Pages (from-to)61-68
Number of pages8
JournalJournal of Medical Ultrasonics
Volume36
Issue number2
DOIs
Publication statusPublished - 2009 Jun

Fingerprint

Acoustics
Doxorubicin
Free Radicals
Fever
Apoptosis
Spin Trapping
U937 Cells
Trypan Blue
Propidium
Spectrophotometry
Annexin A5
Liver Neoplasms
Fluorescein
Contrast Media
Sucrose
Neoplasms
Cell Survival
Flow Cytometry
Hydrolysis
Coloring Agents

Keywords

  • Apoptosis
  • Doxorubicin
  • Low-intensity ultrasound

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Low-intensity ultrasound adjuvant therapy : Enhancement of doxorubicin-induced cytotoxicity and the acoustic mechanisms involved. / Kondo, Takashi; Yoshida, Toru; Ogawa, Ryohei; Hassan, Mariame A.; Furusawa, Yukihiro; Zhao, Qing Li; Watanabe, Akihiko; Morii, Akihiro; Feril, Loreto B.; Tachibana, Katsuro; Kitagawa, Hiroshi; Tabuchi, Yoshiaki; Takasaki, Ichiro; Shehata, Mohammad H.; Kudo, Nobuki; Tsukada, Kazuhiro.

In: Journal of Medical Ultrasonics, Vol. 36, No. 2, 06.2009, p. 61-68.

Research output: Contribution to journalArticle

Kondo, T, Yoshida, T, Ogawa, R, Hassan, MA, Furusawa, Y, Zhao, QL, Watanabe, A, Morii, A, Feril, LB, Tachibana, K, Kitagawa, H, Tabuchi, Y, Takasaki, I, Shehata, MH, Kudo, N & Tsukada, K 2009, 'Low-intensity ultrasound adjuvant therapy: Enhancement of doxorubicin-induced cytotoxicity and the acoustic mechanisms involved', Journal of Medical Ultrasonics, vol. 36, no. 2, pp. 61-68. https://doi.org/10.1007/s10396-009-0212-8
Kondo, Takashi ; Yoshida, Toru ; Ogawa, Ryohei ; Hassan, Mariame A. ; Furusawa, Yukihiro ; Zhao, Qing Li ; Watanabe, Akihiko ; Morii, Akihiro ; Feril, Loreto B. ; Tachibana, Katsuro ; Kitagawa, Hiroshi ; Tabuchi, Yoshiaki ; Takasaki, Ichiro ; Shehata, Mohammad H. ; Kudo, Nobuki ; Tsukada, Kazuhiro. / Low-intensity ultrasound adjuvant therapy : Enhancement of doxorubicin-induced cytotoxicity and the acoustic mechanisms involved. In: Journal of Medical Ultrasonics. 2009 ; Vol. 36, No. 2. pp. 61-68.
@article{26965e841bf841e09427dd3b1f385aac,
title = "Low-intensity ultrasound adjuvant therapy: Enhancement of doxorubicin-induced cytotoxicity and the acoustic mechanisms involved",
abstract = "Purpose: In this study, the effects of low-intensity pulsed ultrasound (LIU) as an adjuvant to doxorubicin (DOX) treatment was further investigated in comparison to hyperthermia as another widely used adjuvant. The effects were compared with respect to cell killing and apoptosis induction in U937 cells. Human primary liver cancer (PLC) cells were also used to evaluate the effects of the combinations. The use of an echo contrast agent was investigated for further enhancement of cytotoxicity. Finally, the acoustic mechanisms involved were investigated. Methods: The effects of different treatment regimens on cell viability were determined using the Trypan blue dye-exclusion test. Apoptosis induction was detected by flow cytometry using fluorescein isothiocyanate- annexin V and propidium iodide staining. The mechanistic study involved electron paramagnetic spin trapping for detecting free radical formation as an indicator of the occurrence of inertial cavitation and spectrophotometry for sucrose hydrolysis as an indicator for noncavitational effects. Results: The combination treatments exerted synergistic effects on cytotoxicity depending on the acoustic conditions used. The use of LIU as an adjuvant to DOX treatment was shown to be superior to the use of hyperthermia as an adjuvant. Moreover, the combination seems to be promising for other cancer types provided that the acoustic conditions are properly selected with respect to drug concentration. The key ultrasound mechanism responsible for the synergism observed was shown to be the production of free radicals by inertial cavitation. Non-cavitational forces were also shown to contribute to the effect. Conclusion: This study is motivating to engage in in vivo research with various cancer types as a step toward clinical applicability and is emphasizing on the importance of developing therapeutic protocols for setting LIU parameters with respect to other therapeutic conditions.",
keywords = "Apoptosis, Doxorubicin, Low-intensity ultrasound",
author = "Takashi Kondo and Toru Yoshida and Ryohei Ogawa and Hassan, {Mariame A.} and Yukihiro Furusawa and Zhao, {Qing Li} and Akihiko Watanabe and Akihiro Morii and Feril, {Loreto B.} and Katsuro Tachibana and Hiroshi Kitagawa and Yoshiaki Tabuchi and Ichiro Takasaki and Shehata, {Mohammad H.} and Nobuki Kudo and Kazuhiro Tsukada",
year = "2009",
month = "6",
doi = "10.1007/s10396-009-0212-8",
language = "English",
volume = "36",
pages = "61--68",
journal = "Japanese Journal of Medical Ultrasonics",
issn = "1346-4523",
publisher = "Springer Japan",
number = "2",

}

TY - JOUR

T1 - Low-intensity ultrasound adjuvant therapy

T2 - Enhancement of doxorubicin-induced cytotoxicity and the acoustic mechanisms involved

AU - Kondo, Takashi

AU - Yoshida, Toru

AU - Ogawa, Ryohei

AU - Hassan, Mariame A.

AU - Furusawa, Yukihiro

AU - Zhao, Qing Li

AU - Watanabe, Akihiko

AU - Morii, Akihiro

AU - Feril, Loreto B.

AU - Tachibana, Katsuro

AU - Kitagawa, Hiroshi

AU - Tabuchi, Yoshiaki

AU - Takasaki, Ichiro

AU - Shehata, Mohammad H.

AU - Kudo, Nobuki

AU - Tsukada, Kazuhiro

PY - 2009/6

Y1 - 2009/6

N2 - Purpose: In this study, the effects of low-intensity pulsed ultrasound (LIU) as an adjuvant to doxorubicin (DOX) treatment was further investigated in comparison to hyperthermia as another widely used adjuvant. The effects were compared with respect to cell killing and apoptosis induction in U937 cells. Human primary liver cancer (PLC) cells were also used to evaluate the effects of the combinations. The use of an echo contrast agent was investigated for further enhancement of cytotoxicity. Finally, the acoustic mechanisms involved were investigated. Methods: The effects of different treatment regimens on cell viability were determined using the Trypan blue dye-exclusion test. Apoptosis induction was detected by flow cytometry using fluorescein isothiocyanate- annexin V and propidium iodide staining. The mechanistic study involved electron paramagnetic spin trapping for detecting free radical formation as an indicator of the occurrence of inertial cavitation and spectrophotometry for sucrose hydrolysis as an indicator for noncavitational effects. Results: The combination treatments exerted synergistic effects on cytotoxicity depending on the acoustic conditions used. The use of LIU as an adjuvant to DOX treatment was shown to be superior to the use of hyperthermia as an adjuvant. Moreover, the combination seems to be promising for other cancer types provided that the acoustic conditions are properly selected with respect to drug concentration. The key ultrasound mechanism responsible for the synergism observed was shown to be the production of free radicals by inertial cavitation. Non-cavitational forces were also shown to contribute to the effect. Conclusion: This study is motivating to engage in in vivo research with various cancer types as a step toward clinical applicability and is emphasizing on the importance of developing therapeutic protocols for setting LIU parameters with respect to other therapeutic conditions.

AB - Purpose: In this study, the effects of low-intensity pulsed ultrasound (LIU) as an adjuvant to doxorubicin (DOX) treatment was further investigated in comparison to hyperthermia as another widely used adjuvant. The effects were compared with respect to cell killing and apoptosis induction in U937 cells. Human primary liver cancer (PLC) cells were also used to evaluate the effects of the combinations. The use of an echo contrast agent was investigated for further enhancement of cytotoxicity. Finally, the acoustic mechanisms involved were investigated. Methods: The effects of different treatment regimens on cell viability were determined using the Trypan blue dye-exclusion test. Apoptosis induction was detected by flow cytometry using fluorescein isothiocyanate- annexin V and propidium iodide staining. The mechanistic study involved electron paramagnetic spin trapping for detecting free radical formation as an indicator of the occurrence of inertial cavitation and spectrophotometry for sucrose hydrolysis as an indicator for noncavitational effects. Results: The combination treatments exerted synergistic effects on cytotoxicity depending on the acoustic conditions used. The use of LIU as an adjuvant to DOX treatment was shown to be superior to the use of hyperthermia as an adjuvant. Moreover, the combination seems to be promising for other cancer types provided that the acoustic conditions are properly selected with respect to drug concentration. The key ultrasound mechanism responsible for the synergism observed was shown to be the production of free radicals by inertial cavitation. Non-cavitational forces were also shown to contribute to the effect. Conclusion: This study is motivating to engage in in vivo research with various cancer types as a step toward clinical applicability and is emphasizing on the importance of developing therapeutic protocols for setting LIU parameters with respect to other therapeutic conditions.

KW - Apoptosis

KW - Doxorubicin

KW - Low-intensity ultrasound

UR - http://www.scopus.com/inward/record.url?scp=67650735885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650735885&partnerID=8YFLogxK

U2 - 10.1007/s10396-009-0212-8

DO - 10.1007/s10396-009-0212-8

M3 - Article

AN - SCOPUS:67650735885

VL - 36

SP - 61

EP - 68

JO - Japanese Journal of Medical Ultrasonics

JF - Japanese Journal of Medical Ultrasonics

SN - 1346-4523

IS - 2

ER -