PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model.

Cisplatinum (CDDP) is a first-line drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 μmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients.

Higuchi T ，Yamamoto J ，Sugisawa N ，Tashiro Y ，Nishino H ，Yamamoto N ，Hayashi K ，Kimura H ，Miwa S ，Igarashi K ，Bouvet M ，Singh SR ，Tsuchiya H ，Hoffman RM ... -  《-》

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

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.

Higuchi T ，Sugisawa N ，Miyake K ，Oshiro H ，Yamamoto N ，Hayashi K ，Kimura H ，Miwa S ，Igarashi K ，Kline Z ，Bouvet M ，Singh SR ，Tsuchiya H ，Hoffman RM ... -  《-》

Pioglitazone modulates doxorubicin resistance in a in vivo model of drug resistant osteosarcoma xenograft.

Natarajan A ，Ramachandran B ，Gopisetty G ，Jayavelu S ，Sundersingh S ，Rajkumar T ... -  《-》

A Novel Anionic-phosphate-platinum Complex Effectively Targets a Cisplatinum-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model.

We have previously developed a novel bone-targeting platinum compound, 3Pt, and showed that it has strong inhibitory activity against osteosarcoma cells and orthotopic cell-line xenograft mouse models. In the present report, we compared the efficacy of 3Pt to cisplatinum (CDDP) in a CDDP-resistant relapsed osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. The tumor of a patient with osteosarcoma of the distal femur was treated with CDDP-based chemotherapy followed by surgery. The surgical specimen was used to establish a PDOX model. An osteosarcoma cell line was also established from the original patient tumor. Osteosarcoma cell viability was assessed with the WST-8 assay and the IC50 values were calculated. The PDOX models were randomized into three groups: untreated control, CDDP-treated group, and 3Pt-treated group. Tumor size and body weight were measured twice a week. 3Pt had a strong concentration-dependent cytocidal effect in vitro. The IC50 value of 3Pt was significantly lower than that of CDDP. On day 14 of the treatment, 3Pt caused a significantly greater tumor growth inhibition compared to the untreated control and CDDP-treated mice. 3Pt is a promising clinical candidate for the treatment of recalcitrant osteosarcoma.

Igarashi K ，Kawaguchi K ，Yamamoto N ，Hayashi K ，Kimura H ，Miwa S ，Higuchi T ，Taniguchi Y ，Yonezawa H ，Araki Y ，Morinaga S ，Misra S ，Nelson SD ，Dry SM ，Li Y ，Odani A ，Singh SR ，Tsuchiya H ，Hoffman RM ... -  《-》

Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemothe

Igarashi K ，Kawaguchi K ，Kiyuna T ，Miyake K ，Miyake M ，Li S ，Han Q ，Tan Y ，Zhao M ，Li Y ，Nelson SD ，Dry SM ，Singh AS ，Elliott IA ，Russell TA ，Eckardt MA ，Yamamoto N ，Hayashi K ，Kimura H ，Miwa S ，Tsuchiya H ，Eilber FC ，Hoffman RM ... -  《-》