Vaid Mudit, Singh Tripti, Prasad Ram, Katiyar Santosh K
Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA.
Int J Oncol. 2016 Feb;48(2):624-34. doi: 10.3892/ijo.2015.3286. Epub 2015 Dec 10.
Melanoma is a highly aggressive form of skin cancer with poor survival rate. Aberrant activation of Wnt/β-catenin has been observed in nearly one-third of human melanoma cases thereby indicating that targeting Wnt/β-catenin signaling could be a promising strategy against melanoma development. In the present study, we determined chemotherapeutic effect of grape seed proanthocyanidins (GSPs) on the growth of melanoma cells and validated their protective effects in vivo using a xenograft mouse model, and assessed if β-catenin is the target of GSP chemotherapeutic effect. Our in vitro data show that treatment of A375 and Hs294t human melanoma cells with GSPs inhibit the growth of melanoma cells, which was associated with the reduction in the levels of β-catenin. Administration of dietary GSPs (0.2 and 0.5%, w/w) in supplementation with AIN76A control diet significantly inhibited the growth of melanoma tumor xenografts in nude mice. Furthermore, dietary GSPs inhibited the xenograft growth of Mel928 (β-catenin-activated), while did not inhibit the xenograft growth of Mel1011 (β-catenin-inactivated) cells. These observations were further verified by siRNA knockdown of β-catenin and forced overexpression of β-catenin in melanoma cells using a cell culture model.
黑色素瘤是一种侵袭性很强的皮肤癌，生存率很低。在近三分之一的人类黑色素瘤病例中观察到Wnt/β-连环蛋白的异常激活，这表明靶向Wnt/β-连环蛋白信号通路可能是对抗黑色素瘤发展的一种有前景的策略。在本研究中，我们确定了葡萄籽原花青素（GSPs）对黑色素瘤细胞生长的化疗作用，并使用异种移植小鼠模型验证了它们在体内的保护作用，还评估了β-连环蛋白是否是GSP化疗作用的靶点。我们的体外数据表明，用GSPs处理A375和Hs294t人黑色素瘤细胞可抑制黑色素瘤细胞的生长，这与β-连环蛋白水平的降低有关。在AIN76A对照饮食中补充膳食GSPs（0.2%和0.5%，w/w）可显著抑制裸鼠体内黑色素瘤肿瘤异种移植的生长。此外，膳食GSPs抑制了Mel928（β-连环蛋白激活）的异种移植生长，而没有抑制Mel1011（β-连环蛋白失活）细胞的异种移植生长。使用细胞培养模型对β-连环蛋白进行小干扰RNA敲低和在黑色素瘤细胞中强制过表达β-连环蛋白，进一步验证了这些观察结果。
