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.
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。
