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Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression.
Biomed Pharmacother. 2019 Oct; 118:109356.BP

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+Show Affiliations

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.AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA.Department of Surgery, University of California, San Diego, CA, 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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31545293

Citation

Higuchi, Takashi, et al. "Pioglitazone, an Agonist of PPARγ, Reverses Doxorubicin-resistance in an Osteosarcoma Patient-derived Orthotopic Xenograft Model By Downregulating P-glycoprotein Expression." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 118, 2019, p. 109356.
Higuchi T, Sugisawa N, Miyake K, et al. Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression. Biomed Pharmacother. 2019;118:109356.
Higuchi, T., Sugisawa, N., Miyake, K., Oshiro, H., Yamamoto, N., Hayashi, K., Kimura, H., Miwa, S., Igarashi, K., Kline, Z., Bouvet, M., Singh, S. R., Tsuchiya, H., & Hoffman, R. M. (2019). Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 118, 109356. https://doi.org/10.1016/j.biopha.2019.109356
Higuchi T, et al. Pioglitazone, an Agonist of PPARγ, Reverses Doxorubicin-resistance in an Osteosarcoma Patient-derived Orthotopic Xenograft Model By Downregulating P-glycoprotein Expression. Biomed Pharmacother. 2019;118:109356. PubMed PMID: 31545293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression. AU - Higuchi,Takashi, AU - Sugisawa,Norihiko, AU - Miyake,Kentaro, AU - Oshiro,Hiromichi, AU - Yamamoto,Norio, AU - Hayashi,Katsuhiro, AU - Kimura,Hiroaki, AU - Miwa,Shinji, AU - Igarashi,Kentaro, AU - Kline,Zoey, AU - Bouvet,Michael, AU - Singh,Shree Ram, AU - Tsuchiya,Hiroyuki, AU - Hoffman,Robert M, Y1 - 2019/08/22/ PY - 2019/07/23/received PY - 2019/08/09/revised PY - 2019/08/14/accepted PY - 2019/9/24/entrez PY - 2019/9/24/pubmed PY - 2019/9/24/medline KW - Doxorubicin KW - Drug resistancy KW - Orthotopic xenograft KW - Osteosarcoma KW - PDOX KW - PPARγ KW - Patient-derived KW - Pioglitazone SP - 109356 EP - 109356 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed. Pharmacother. VL - 118 N2 - 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. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/31545293/Pioglitazone_an_agonist_of_PPARγ_reverses_doxorubicin_resistance_in_an_osteosarcoma_patient_derived_orthotopic_xenograft_model_by_downregulating_P_glycoprotein_expression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(19)33594-2 DB - PRIME DP - Unbound Medicine ER -