Department of Molecular Oncology, Cancer Institute (WIA), Chennai, 600036, India.
Department of Oncopathology, Cancer Institute (WIA), Chennai, India.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Feb;394(2):361-371. doi: 10.1007/s00210-020-01982-3. Epub 2020 Oct 5.
Osteosarcoma has been reported with treatment failure in up to 40% of cases. Our laboratory had identified genes involved in the PPARγ pathway to be associated with doxorubicin (DOX) resistance. We hence used PPARγ agonist pioglitazone (PIO) to modulate DOX resistance. DOX-resistant cell line (143B-DOX) was developed by gradient exposure to DOX. The cytotoxicity to PIO and in combination with DOX was assayed in vitro, followed by HPLC to estimate the metabolites of PIO in the presence of microsomes (HLMs). Gene expression studies revealed the mechanism behind the cytotoxicity of PIO. Further, the effects were evaluated in mice bearing 143B-DOX tumors treated either with PIO (20 mg/kg/p.o or 40 mg/kg/p.o Q1D) alone or in combination with DOX (0.5 mg/kg/i.p Q2W). 143B-DOX was 50-fold resistant over parental cells. While PIO did not show any activity on its own, the addition of HLMs to the cells in culture showed over 80% cell kill within 24 h, possibly due to the metabolites of PIO as determined by HPLC. In combination with DOX, PIO had shown synergistic activity. Additionally, cytotoxicity assay in the presence of HLMs revealed that PIO on its own showed promising activity compared to its metabolites-hydroxy pioglitazone and keto pioglitazone. In vivo studies demonstrated that treatment with 40 mg/kg/p.o PIO alone showed significant activity, followed by a combination with DOX. Gene expression studies revealed that PIO could modulate drug resistance by downregulating MDR1 and IL8. Our study suggests that PIO can modulate DOX resistance in osteosarcoma cells.
骨肉瘤的治疗失败率高达 40%。我们的实验室已经确定参与 PPARγ 途径的基因与多柔比星（DOX）耐药有关。因此，我们使用 PPARγ 激动剂吡格列酮（PIO）来调节 DOX 耐药性。通过梯度暴露于 DOX 开发了 DOX 耐药细胞系（143B-DOX）。在体外测定 PIO 及其与 DOX 联合的细胞毒性，然后用 HPLC 估计在微粒体（HLMs）存在下 PIO 的代谢物。基因表达研究揭示了 PIO 细胞毒性的机制。此外，在接受 143B-DOX 肿瘤治疗的小鼠中评估了单独使用 PIO（20 mg/kg/p.o 或 40 mg/kg/p.o Q1D）或与 DOX（0.5 mg/kg/i.p Q2W）联合使用的效果。143B-DOX 对亲本细胞的耐药性增加了 50 倍。虽然 PIO 本身没有任何活性，但在培养细胞中添加 HLMs 可在 24 小时内导致超过 80%的细胞死亡，这可能是由于 HPLC 确定的 PIO 代谢物所致。与 DOX 联合使用时，PIO 表现出协同活性。此外，在 HLMs 存在下进行的细胞毒性测定表明，与代谢物羟吡格列酮和酮吡格列酮相比，PIO 本身具有很有前途的活性。体内研究表明，单独使用 40 mg/kg/p.o PIO 治疗表现出显著的活性，随后与 DOX 联合使用。基因表达研究表明，PIO 可以通过下调 MDR1 和 IL8 来调节药物耐药性。我们的研究表明，PIO 可以调节骨肉瘤细胞中的 DOX 耐药性。
