本芴醇衍生物LY980503逆转人乳腺癌多药耐药细胞株MCF/DOX对多柔比星的耐药性

Reversal of resistance of multidrug resistant MCF/Dox cell line to doxorubicin by a benflumetol derivative LY980503

目的 探讨本芴醇衍生物LY980 5 0 3对肿瘤多药耐药的逆转作用及其作用机理。方法 采用噻唑蓝 (MTT)法检测细胞毒作用 ;采用流式细胞术测定细胞内多柔比星 (Dox)浓度 ;应用人乳腺癌裸鼠移植瘤模型研究LY980 5 0 3对肿瘤多药耐药的体内逆转作用。结果 LY980 5 0 3在 4 .0 μmol·L- 1(非细胞毒剂量 )能大部逆转人乳腺癌耐Dox细胞株MCF/Dox对Dox的耐药性 ;药物蓄积实验表明 ,LY980 5 0 3能显著增加MCF/Dox细胞内Dox蓄积 ;10 μmol·L- 1LY980 5 0 3作用 96h能明显抑制MCF/Dox细胞mdr 1基因表达水平。将MCF/Dox细胞接种于裸鼠皮下 ,接种后d 4 2 ,合用LY980 5 0 3(2 0 0mg·kg- 1·d- 1×3,ig)的移植瘤体积 (0 .34± 0 .19)cm3较单用Dox的移植瘤体积 (0 .90± 0 .32 )cm3显著缩小。结论LY980 5 0 3在体外及体内均能有效逆转MCF/Dox细胞对Dox的耐药性。

AIM To investigate the reversing effect of LY980503 (a benflumetol derivative) on multidrug resistance of MCF/Dox cell line and its mechanism. METHODS The cytotoxicity of doxorubicin(Dox) in vitro was assayed by 3 (4,5 dimethylthiazol 2 yl) 2,5 diphenyltetrazolium bro mide method. Intracellular Dox concentration was measured by flow cytometry. Reverse transcription polymerase chain reaction(RT PCR) method was used to measure the expression level of mdr 1 gene. The xenograft model in nude mice was used to investigate the effect of LY980503 on the antitumor activity of Dox in vivo. RESULTS At non cytotoxic concentrations, LY980503 potentiated the cytotoxicity of Dox in a dose dependent manner in MCF/Dox cells. LY980503 at 4.0 μmol·L -1 mostly reversed resistance against Dox in MCF/Dox cells. In resistant cells, LY980503 increased Dox accumulation in a dose dependent manner. Besides, LY980503 could significantly inhibit the expression of mdr 1 gene of MCF/Dox cells. Oral administration of LY980503 (200 mg·kg -1 ·d -1 ×3) combined with DOX significantly decreased the volume of xenograft tumor in MCF/Dox bearing nude mice. CONCLUSION LY980503 can effectively reversed the resistance of MCF/Dox cells to Dox in vitro and in vivo.