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

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 (PPARγ) is a nuclear receptor involved in cellular differentiation and proliferation. Recently, a correlation between the expression and activity of PPARγ and the expression of P-gp-associated with MDR, has been reported in several human cancers. The present study determined if pioglitazone (PIO), a PPARγ 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.

• Authors: Takashi Higuchi, Norihiko Sugisawa, Kentaro Miyake, Hiromichi Oshiro, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi, Zoey Kline, Michael Bouvet, Shree Ram Singh, Hiroyuki Tsuchiya, Robert M Hoffman
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 118 Pg. 109356 (Oct 2019) ISSN: 1950-6007 [Electronic] France
• PMID: 31545293 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Ki-67 Antigen
• PPAR gamma
• RNA, Messenger
• Doxorubicin
• Pioglitazone

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Adolescent
• Animals
• Body Weight (drug effects)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Doxorubicin (therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Ki-67 Antigen (metabolism)
• Male
• Mice, Nude
• Osteosarcoma (drug therapy, genetics, pathology)
• PPAR gamma (agonists, metabolism)
• Pioglitazone (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays