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Pioglitazone, an agonist of PPAR?, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression

  1. Author:
    Higuchi, Takashi
    Sugisawa, Norihiko
    Miyake, Kentaro
    Oshiro, Hiromichi
    Yamamoto, Norio
    Hayashi, Katsuhiro
    Kimura, Hiroaki
    Miwa, Shinji
    Igarashi, Kentaro
    Kline,Zoey
    Bouvet, Michael
    Singh,Shree Ram
    Tsuchiya, Hiroyuki
    Hoffman, Robert M

  2. Author Address

    AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan., AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA., Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA., Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: singhshr@mail.nih.gov., Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan. Electronic address: tsuchi@med.kanazawa-u.ac.jp., AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA. Electronic address: all@anticancer.com.,
    1. Year: 2019
    2. Date: Oct
    3. Epub Date: 2019 08 22
  2. Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
    1. 118
    2. Pages: 109356
  4. Type of Article: Article
  5. Article Number: 109356
  6. ISSN: 0753-3322
  1. Abstract:

    Multidrug resistance (MDR) which results in chemoresistance is a major problem in osteosarcoma. P-glycoprotein (P-gp) plays a critical role in MDR by pumping out chemotherapy agents. Peroxisome proliferator activated receptor gamma (PPAR?) is a nuclear receptor involved in cellular differentiation and proliferation. Recently, a correlation between the expression and activity of PPAR? and the expression of P-gp-associated with MDR, has been reported in several human cancers. The present study determined if pioglitazone (PIO), a PPAR? agonist, could modulate P-gp and overcome doxorubicin (DOX)-resistance in a patient-derived orthotopic xenograft (PDOX) model of osteosarcoma. P-gp mRNA expression was quantified in 143B human osteosarcoma cells treated with DOX with/without PIO. The osteosarcoma PDOX models were randomized into four treatment groups of six mice: Control; PIO alone; DOX alone; DOX and PIO combination. Tumor size and body weight were measured during the 14 days of treatment. DOX significantly induced P-gp mRNA in a dose-dependent manner in 143B cells. PIO inhibited the increase of P-gp mRNA induced by DOX treatment when co-administrated with DOX. Tumor growth was inhibited the most by the DOX-PIO combination. Tumors treated with the DOX-PIO combination also had the most tumor necrosis. This study suggests that the DOX-PIO combination could be used in the clinic for osteosarcoma patients who develop DOX-resistance. Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.biopha.2019.109356
  3. PMID: 31545293
  4. View record in Web of Science®
  5. WOS: 000486395000145
  6. PII : S0753-3322(19)33594-2

Library Notes

  1. Fiscal Year: FY2019-2020
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