吡格列酮是过氧化物酶体增殖物激活受体 γ 的激动剂，通过下调 P-糖蛋白的表达逆转骨肉瘤患者来源的原位异种移植模型中的多柔比星耐药性。
Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression.
机构信息
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.
出版信息
Biomed Pharmacother. 2019 Oct;118:109356. doi: 10.1016/j.biopha.2019.109356. Epub 2019 Aug 22.
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.
多药耐药（MDR）导致化疗耐药是骨肉瘤的主要问题。P 糖蛋白（P-gp）通过泵出化疗药物在 MDR 中起关键作用。过氧化物酶体增殖物激活受体γ（PPARγ）是一种参与细胞分化和增殖的核受体。最近，有报道称，在几种人类癌症中，PPARγ 的表达和活性与与 MDR 相关的 P-gp 表达之间存在相关性。本研究旨在确定吡格列酮（PIO），一种 PPARγ 激动剂，是否可以调节 P-gp 并克服骨肉瘤患者来源的原位异种移植（PDOX）模型中的多柔比星（DOX）耐药性。用 DOX 处理 143B 人骨肉瘤细胞后，定量检测 P-gp mRNA 表达。将骨肉瘤 PDOX 模型随机分为四组，每组 6 只小鼠：对照组；PIO 单独治疗；DOX 单独治疗；DOX 和 PIO 联合治疗。在 14 天的治疗过程中测量肿瘤大小和体重。DOX 在 143B 细胞中呈剂量依赖性方式显著诱导 P-gp mRNA。当与 DOX 联合使用时，PIO 抑制 DOX 处理诱导的 P-gp mRNA 增加。DOX-PIO 联合治疗最能抑制肿瘤生长。用 DOX-PIO 联合治疗的肿瘤也有最多的肿瘤坏死。本研究表明，对于发生 DOX 耐药的骨肉瘤患者，DOX-PIO 联合治疗可在临床上使用。
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