目的：探讨姜黄素及其代谢产物四氢姜黄素对乳腺癌多柔比星耐药细胞MCF-7/ADR耐药性的逆转作用及其可能机制。方法：采用CCK-8法检测姜黄素和四氢姜黄素对MCF-7/ADR细胞增殖的抑制作用及对多柔比星耐药性的逆转作用；采用划痕愈合实验和Transwell实验分别检测细胞迁移和侵袭能力；采用流式细胞术检测细胞凋亡；采用实时荧光定量PCR和WB法分别检测谷胱甘肽S-转移酶π-1（GSTP1）、Janus激酶1（JAK1）和信号转导与转录激活因子3（STAT3）mRNA，以及GSTP1、JAK1、磷酸化JAK1（p-JAK1）、STAT3 和磷酸化STAT3（p-STAT3）蛋白的表达。结果：姜黄素和四氢姜黄素均呈浓度依赖性抑制MCF-7/ADR细胞增殖，四氢姜黄素的IC50为（18.62 ± 2.15）μmol/L，显著低于姜黄素的（37.45 ± 3.28）μmol/L（P < 0.05）；两者均可增强多柔比星对MCF-7/ADR细胞增殖的抑制作用，四氢姜黄素的耐药逆转指数（4.82）高于姜黄素（2.96）（P < 0.05）。两种药物均呈浓度依赖性抑制MCF-7/ADR 细胞迁移和侵袭并促进细胞凋亡，同时下调GSTP1、JAK1和STAT3 mRNA，以及GSTP1、p-JAK1和p-STAT3蛋白的表达（与0 μmol/L组相比，均P < 0.05）。与0 μmol/L组相比，80 μmol/L姜黄素或四氢姜黄素处理后，细胞划痕愈合率和侵袭细胞数均显著降低，细胞凋亡率显著升高（均P < 0.05）。结论：姜黄素及其代谢产物四氢姜黄素可逆转乳腺癌MCF-7/ADR 细胞对多柔比星的耐药性，其机制可能与抑制细胞迁移和侵袭、促进细胞凋亡、下调GSTP1 表达，以及抑制JAK1和STAT3的磷酸化有关。

Objective: To investigate the effects of curcumin and its metabolite tetrahydrocurcumin on reversing doxorubicin resistance in MCF-7/ADR breast cancer cells and to explore the possible mechanisms. Methods: The inhibitory effects of curcumin and tetrahydrocurcumin on MCF-7/ADR cell proliferation and their effects on the reversal of doxorubicin resistance were assessed using the CCK-8 assay. Cell migration and invasion were evaluated using wound-healing and Transwell assays, respectively. Apoptosis was analyzed by flow cytometry. The mRNA levels of glutathione S-transferase pi 1 (GSTP1), Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3), as well as the protein levels of GSTP1, JAK1, phosphorylated JAK1 (p-JAK1), STAT3, and phosphorylated STAT3 (p-STAT3), were measured by quantitative real-time PCR and WB assay, respectively. Results: Both curcumin and tetrahydrocurcumin inhibited MCF-7/ADR cell proliferation in a concentration-dependent manner. The IC?? of tetrahydrocurcumin (18.62 ± 2.15) μmol/L was significantly lower than that of curcumin (37.45 ± 3.28) μmol/L (P < 0.05). Both compounds enhanced the inhibitory effect of doxorubicin on MCF-7/ADR cell proliferation, and the resistance reversal index of tetrahydrocurcumin (4.82) was significantly higher than that of curcumin (2.96) (P < 0.05). Compared with the 0 μmol/L groups, both compounds inhibited MCF-7/ADR cell migration and invasion in a concentration-dependent manner, promoted apoptosis, and downregulated GSTP1, JAK1, and STAT3 mRNA expression as well as GSTP1, p-JAK1, and p-STAT3 protein expression (all P < 0.05). Treatment with 80 μmol/L curcumin or tetrahydrocurcumin significantly reduced the wound-healing rate and the number of invading cells and significantly increased the apoptosis rate (all P < 0.05). Conclusion: Curcumin and its metabolite tetrahydrocurcumin can reverse doxorubicin resistance in MCF-7/ADR breast cancer cells, possibly by inhibiting cell migration and invasion, promoting apoptosis, downregulating GSTP1 expression, and suppressing the phosphorylation of JAK1 and STAT3.

国家自然科学基金（82274221）；天津市医学重点学科（专科）建设项目（TJYXZDXK-009A）