Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VIIM, Kolkata, West Bengal, 700054, India.
The Bioinformatics Center, Bose Institute, Kolkata, West Bengal, 700054, India.
Cell Death Dis. 2018 May 1;9(5):448. doi: 10.1038/s41419-018-0476-2.
Resveratrol, a trans-stilbene polyphenolic compound and its synthetic analogs are widely used bioactive molecules due to their remarkable chemo-preventive potential. Here, we have identified a novel synthetic trans-stilbene compound, Z-DAN-11 ((Z)-3-(3, 4-dimethoxyphenyl)-2-(3, 4, 5-trimethoxyphenyl) acrylonitrile) which shows remarkable efficacy in blocking tumor growth and progression both in vitro and in vivo. Z-DAN-11 inhibits proliferation of cancer cells in vitro through microtubule depolymerization that induced G2/M arrest and consequently leads to apoptotic cell death. More importantly, Z-DAN-11 shows limited cytotoxicity to normal cells as compared to cancer cells. Quite interestingly, we have found that Z-DAN-11-mediated ROS production helps in dramatic alteration in the mitochondrial redox status which critically contributes to the apoptosis. Mechanistic studies reveal that Z-DAN-11 induces the expression of pro-apoptotic proteins and decreases anti-apoptotic protein expression that decisively helps in the activation of caspase 8, caspase 9, and caspase 3, leading to cleavage of PARP1 and cell death via intrinsic and extrinsic pathways of apoptosis. Moreover, Z-DAN-11-mediated apoptosis of cancer cells is through a partial p53-dependent pathway, since both HCT116 p53 cells as well as p53-silenced cells (siRNA) were able to block apoptosis partially but significantly. Importantly, Z-DAN-11 also imparts its anti-tumorigenic effect by inhibiting clonogenic property and anchorage-independent growth potential of cancer cells at concentrations at least 10 times lower than that required for inducing apoptosis. Finally, in vivo study with immuno-competent syngeneic mice shows Z-DAN-11 to be able to impede tumor progression without any adverse side-effects. Hence, we identified a novel, synthetic trans-stilbene derivative with anti-tumorigenic potential which might tremendously help in devising potential therapeutic strategy against cancer.
白藜芦醇是一种反式二苯乙烯多酚化合物及其合成类似物，由于其显著的化学预防潜力，被广泛用作生物活性分子。在这里，我们鉴定了一种新型的合成反式二苯乙烯化合物 Z-DAN-11((Z)-3-(3,4-二甲氧基苯基)-2-(3,4,5-三甲氧基苯基)丙烯腈)，它在体外和体内都显示出显著的抑制肿瘤生长和进展的疗效。Z-DAN-11 通过微管解聚抑制癌细胞的体外增殖，导致 G2/M 期阻滞，进而导致细胞凋亡。更重要的是，与癌细胞相比，Z-DAN-11 对正常细胞的细胞毒性有限。有趣的是，我们发现 Z-DAN-11 介导的 ROS 产生有助于线粒体氧化还原状态的剧烈改变，这对细胞凋亡至关重要。机制研究表明，Z-DAN-11 诱导促凋亡蛋白的表达，降低抗凋亡蛋白的表达，从而有效地激活 caspase 8、caspase 9 和 caspase 3，导致 PARP1 的切割和细胞死亡通过细胞凋亡的内在和外在途径。此外，Z-DAN-11 通过部分依赖 p53 的途径诱导癌细胞凋亡，因为 HCT116 p53 细胞和 p53 沉默细胞(siRNA)都能够部分但显著地阻断凋亡。重要的是，Z-DAN-11 还通过抑制癌细胞的集落形成能力和锚定非依赖性生长潜力，在至少低 10 倍于诱导凋亡所需的浓度下发挥其抗肿瘤作用。最后，在免疫功能正常的同种异体小鼠体内研究表明，Z-DAN-11 能够在没有任何不良反应的情况下阻止肿瘤进展。因此，我们鉴定了一种具有抗肿瘤潜力的新型合成反式二苯乙烯衍生物，这可能极大地有助于制定针对癌症的潜在治疗策略。
