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

https://doi.org/10.1016/j.biopha.2019.109356Get rights and content
Under a Creative Commons license
open access

Highlights

  • PPARγ agonist pioglitazone reverses DOX-resistance in osteosarcoma PDOX.

  • Pioglitazone modulate P-glycoprotein and overcome DOX-resistance in osteosarcoma PDOX.

  • DOX-Pioglitazone combination arrests DOX-resistance osteosarcoma PDOX.

  • No significant body weight loss or animal deaths seen after Pioglitazone treatment.

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.

Keywords

Osteosarcoma
Pioglitazone
Doxorubicin
Drug resistancy
Patient-derived
Orthotopic xenograft
PDOX
PPARγ

Cited by (0)