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首页> 外文期刊>Biochemical Pharmacology >Efflux inhibition by IWR-1-endo confers sensitivity to doxorubicin effects in osteosarcoma cells
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Efflux inhibition by IWR-1-endo confers sensitivity to doxorubicin effects in osteosarcoma cells

机译：IWR-1-endo的抑制抑制促进骨肉瘤细胞中对多柔比星效应的敏感性

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Osteosarcoma is the most common bone tumor that affects children and young adults. Despite advances in the use of combination chemotherapy regimens, response to neoadjuvant chemotherapy in osteosarcoma remains a key determinant of patient outcome. Recently, highly potent small molecule inhibitors of canonical Wnt signaling through the poly(ADP-ribose) polymerase (PARP)-family enzymes, tankyrases 1 & 2 (Tnksl/2), have been considered as possible chemotherapy sensitizing agents. The goal of this study was to determine the ability of the highly specific Tnks1/2 inhibitor IWR-1-endo to sensitize chemotherapy-resistant osteosarcoma to doxorubicin. We found that IWR-1-endo significantly inhibited cellular efflux, as measured by cellular retention of Calcein AM and doxorubicin. In a model of doxorubicin resistant osteosarcoma, pre-treatment with IWR-1-endo strongly sensitized to doxorubicin. This sensitization reduced the doxorubicin IC50 in doxorubicin-resistant cells, but not in chemotherapy na ve cells and caused doxorubicin-treated cells to accumulate at the G2/M checkpoint. Further, we found that sensitization with IWR-1-endo produced increased yH2AX foci formation, indicating increased DNA damage by doxorubicin. Taken together, our findings show that IWR-1-endo increases cellular responses to doxorubicin, by blocking efflux transport in a drug-resistant model of osteosarcoma.
机译：骨肉瘤是影响儿童和年轻成年人的最常见的骨肿瘤。尽管使用组合化疗方案的使用进展，但对骨肉瘤中新辅助化疗的反应仍然是患者结果的关键决定因素。最近，通过聚（ADP-核糖）聚合酶（PARP） - 细胞酶（PARP），油脂酶1和2（TNKSL / 2）的高效小分子抑制剂被认为是可能的化疗敏化剂。本研究的目标是确定高度特异性TNKS1 / 2抑制剂IWR-1-ENDO对多柔比星敏化化疗抗性骨肉瘤的能力。我们发现IWR-1-endo显着抑制细胞流出，通过细胞保留Calcein AM和Doxorubicin来测量。在多柔比星抗性骨肉瘤的模型中，用IWR-1-endo预处理对多柔比星进行预处理。这种敏化性在多柔枯蛋白型电池中减少了多柔比蛋白IC50，但不在化疗Na Ve细胞中，并导致多柔比蛋白处理的细胞在G2 / M检查点累积。此外，我们发现与IWR-1-ENDO产生的致敏产生的YH2AX焦胶质形成增加，表明DOXORUBICIN的DNA损伤增加。我们的研究结果表明，通过阻止骨肉瘤的耐药模型中的流出输送，IWR-1-ENDO增加对多柔比星的细胞反应。

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