Nilotinib counteracts P-glycoprotein-mediated multidrug resistance and synergizes the antitumoral effect of doxorubicin in soft tissue sarcomas.
Nilotinib counteracts P-glycoprotein-mediated multidrug resistance and synergizes the antitumoral effect of doxorubicin in soft tissue sarcomas.
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DOI：
10.1371/journal.pone.0037735
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Alemany R
中科院分区：
文献类型：
--
作者：
Villar VH;Vögler O;Martínez-Serra J;Ramos R;Calabuig-Fariñas S;Gutiérrez A;Barceló F;Martín-Broto J;Alemany R
阿霉素（DXR）在治疗软组织肉瘤（STS）中的治疗效果受到其毒性和多药耐药（MDR）的发展的限制，后者主要由外排泵（例如，P-糖蛋白[P-gp]）。因此，寻找替代疗法，使这些肿瘤对化疗敏感，同时保持低毒性，是一种合理的方法。我们评估了酪氨酸激酶抑制剂尼洛替尼和伊马替尼作为单药或与DXR联合应用在人滑膜肉瘤SW 982和平滑肌肉瘤SK-UT-1细胞中的抗增殖作用的有效性和分子机制。作为单一化合物，尼洛替尼（1-10 µM）比伊马替尼更有效地抑制SK-UT-1和SW 982细胞的生长，抑制率分别为33.5%-59.6%。重要的是，根据等效线分析，只有尼洛替尼可将DXR（0.05-0.5 µM）的抗肿瘤作用协同至少2倍，这明显超过了单纯的作用总和。此外，与单独DXR相比，尼洛替尼联合DXR对细胞数量的影响持续存在（−70.3±5.8%），甚至在停药后12天。在分子水平上，仅尼洛替尼完全阻断FBS诱导的ERK 1和p38 MAPK活化，因此降低了基础和DXR诱导的P-gp水平上调。此外，MDR相关蛋白P-gp和MRP-1的外排活性受到抑制，从而导致细胞内DXR滞留。在高危STS肿瘤中P-gp和MRP-1的阳性表达率分别为53.8%和15.4%，滑膜肉瘤中P-gp的阳性表达率较高（72.7%）。总之，尼洛替尼对STS的细胞模型具有抗增殖作用，并通过逆转DXR诱导的P-gp介导的MDR和抑制MRP-1活性使其对DXR敏感，从而产生具有临床治疗潜力的协同效应。
The therapeutic effect of doxorubicin (DXR) in the treatment of soft tissue sarcomas (STS) is limited by its toxicity and the development of multidrug resistance (MDR), the latter mainly induced by high expression of efflux pumps (e.g., P-glycoprotein [P-gp]). Therefore, the search for alternative therapies, which sensitize these tumors to chemotherapy while maintaining a low toxicity profile, is a rational approach. We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of the tyrosine kinase inhibitors, nilotinib and imatinib, as single agents or in combination with DXR, in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound nilotinib (1–10 µM) was more potent than imatinib inhibiting the growth of SK-UT-1 and SW982 cells by 33.5–59.6%, respectively. Importantly, only nilotinib synergized the antitumoral effect of DXR (0.05–0.5 µM) by at least 2-fold, which clearly surpassed the mere sum of effects according to isobolographic analysis. Moreover, nilotinib in combination with DXR had a sustained effect on cell number (−70.3±5.8%) even 12 days after withdrawal of drugs compared to DXR alone. On the molecular level, only nilotinib fully blocked FBS-induced ERK1 and p38 MAPK activation, hence, reducing basal and DXR-induced up-regulation of P-gp levels. Moreover, efflux activity of the MDR-related proteins P-gp and MRP-1 was inhibited, altogether resulting in intracellular DXR retention. In high-risk STS tumors 53.8% and 15.4% were positive for P-gp and MRP-1 expression, respectively, with high incidence of P-gp in synovial sarcoma (72.7%). In summary, nilotinib exhibits antiproliferative effects on cellular models of STS and sensitizes them to DXR by reverting DXR-induced P-gp-mediated MDR and inhibiting MRP-1 activity, leading to a synergistic effect with potential for clinical treatment.
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影响因子：
8.4
作者：
Debiec-Rychter, M;Dumez, H;van Oosterom, AT
通讯作者：
van Oosterom, AT
影响因子：
8
作者：
Mahadevan, D.;Cooke, L.;Bearss, D.
通讯作者：
Bearss, D.
影响因子：
11.4
作者：
Hochhaus, A.;O'Brien, S. G.;Larson, R. A.
通讯作者：
Larson, R. A.
影响因子：
3.4
作者：
Homet Moreno, Blanca;Garralda Cabanas, Elena;Hitt, Ricardo
通讯作者：
Hitt, Ricardo
影响因子：
11.5
作者：
Gonz치lez, I;Andreu, EJ;de Alava, E
通讯作者：
de Alava, E