Department of Clinical Chemistry and Clinical Biochemistry, Surgical Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
Mol Cancer. 2009 Dec 23;8:129. doi: 10.1186/1476-4598-8-129.
Curcumin induces apoptosis in many cancer cells and it reduces xenograft growth and the formation of lung metastases in nude mice. Moreover, the plant derived polyphenol has been reported to be able to overcome drug resistance to classical chemotherapy. These features render the drug a promising candidate for tumor therapy especially for cancers known for their high rates concerning therapy resistance like melanoma.
We show here that the melanoma cell line M14 is resistant to Curcumin induced apoptosis, which correlates with the absence of any effect on NFkappaB signaling. We show that CXCL1 a chemokine that is down regulated in breast cancer cells by Curcumin in an NFkappaB dependent manner is expressed at variable levels in human melanomas. Yet in M14 cells, CXCL1 expression did not change upon Curcumin treatment. Following the hypothesis that Curcumin is rapidly removed from the resistant cells, we analyzed expression of known multi drug resistance genes and cellular transporters in M14 melanoma cells and in the Curcumin sensitive breast cancer cell line MDA-MB-231. ATP-binding cassette transporter ABCA1, a gene involved in the cellular lipid removal pathway is over-expressed in resistant M14 melanoma as compared to the sensitive MDA-MB-231 breast cancer cells. Gene silencing of ABCA1 by siRNA sensitizes M14 cells to the apoptotic effect of Curcumin most likely as a result of reduced basal levels of active NFkappaB. Moreover, ABCA1 silencing alone also induces apoptosis and reduces p65 expression.
Resistance to Curcumin thus follows classical pathways and ABCA1 expression should be considered as response marker.
姜黄素可诱导许多癌细胞凋亡，减少裸鼠异种移植物生长和肺转移的形成。此外，这种植物来源的多酚已被报道能够克服对经典化疗的耐药性。这些特性使该药物成为肿瘤治疗的有前途的候选药物，特别是对于那些对治疗具有高耐药率的癌症，如黑色素瘤。
我们在这里表明，黑色素瘤细胞系 M14 对姜黄素诱导的细胞凋亡具有抗性，这与 NFκB 信号通路没有任何影响相关。我们表明，姜黄素以 NFκB 依赖性方式下调乳腺癌细胞中的趋化因子 CXCL1，在人黑色素瘤中呈不同水平表达。然而，在 M14 细胞中，姜黄素处理后 CXCL1 的表达没有变化。基于姜黄素从耐药细胞中迅速被清除的假设，我们分析了 M14 黑色素瘤细胞和姜黄素敏感的乳腺癌细胞系 MDA-MB-231 中已知的多药耐药基因和细胞转运蛋白的表达。ATP 结合盒转运体 ABCA1 是参与细胞脂质清除途径的基因，在耐药性 M14 黑色素瘤细胞中表达高于敏感的 MDA-MB-231 乳腺癌细胞。用 siRNA 基因沉默 ABCA1 可使 M14 细胞对姜黄素的凋亡作用敏感，这很可能是由于 NFκB 的活性基础水平降低。此外，单独的 ABCA1 沉默也可诱导细胞凋亡并降低 p65 的表达。
因此，对姜黄素的耐药性遵循经典途径，ABCA1 的表达应被视为反应标志物。
