RSL3 is identified as a potent ferroptosis-triggering agent, which is dependent on the activity of GPX4. RSL3 behaved as an inhibitor of GPX4, reducing the expression of GPX4 and inducing ferroptotic death of head and neck cancer cell[1]
In vitro study demonstrated that RSL3 have a degree of synthetic lethality with oncogenic RAS. RSL3 showed rapid and potent ability to induce synthetic lethality with oncogenic RAS. RSL3 inhibited the growth of BJ-TERT/LT/ST/RASV12 and DRD cells as low as 10 ng/ml and started to kill sensitive cells as early as 8 h after treatment. The growth inhibitory effect and the selectivity of RSL3 were confirmed by trypan blue exclusion assay, which demonstrated the potency and selectivity of RSL3. Moreover, longer treatment with RSL3 had little effect on the viability of cells lacking oncogenic RAS, confirming the qualitative nature of RSL3’s selectivity.[2]
In vivo study determined that RSL3-induced ferroptosis could be enhanced by cetuximab with the mechanism of suppressing the Nrf2/HO-1 axis. A DLD-1 xenograft nude mouse model was established to further explored whether cetuximab promotes RSL3-induced ferroptosis in vivo. All the mice survived well after cell implantation or were treated with vehicle, RSL3, cetuximab, or RSL3 in combination with cetuximab. However, administration of RSL3 alone and treatment with both RSL3 and cetuximab led to a decrease in tumour size and tumour volume. Meanwhile, the relative levels of Nrf2 and HO-1 were decreased and that keap1 expressed was relatively increased after co-treatment with RSL3 and cetuximab.[3]
References:
[1]. Sui X, et al. RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer. Front Pharmacol. 2018 Nov 22;9:1371.
[2]. Shin D, et al. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018 Dec;129:454-462.
[3]. Yang J, et al. Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer. Cell Death Dis. 2021 Nov 13;12(11):1079.
RSL3被认为是一种强效的诱导铁死亡剂，其作用依赖于GPX4的活性。RSL3表现出抑制GPX4的作用，降低了GPX4的表达，并引发头颈癌细胞的铁死亡[1]。
体外研究表明，RSL3与致癌的RAS具有一定程度的合成致死性。 RSL3显示出快速而强大的能力，可以诱导与致癌RAS的合成致死性。 RSL3抑制BJ-TERT / LT / ST / RASV12和DRD细胞的生长，低至10 ng/ml，并在治疗后8小时开始杀死敏感细胞。 通过尝试蓝染色排除实验证实了RSL3的生长抑制作用和选择性，这证明了RSL3的效力和选择性。 此外，较长时间使用RSL3对缺乏致癌RAS细胞的存活率几乎没有影响，从而确认了其选择性质量。 [2]
实验结果表明，通过抑制Nrf2/HO-1轴的机制，Cetuximab可以增强RSL3诱导的铁死亡。为了进一步探究Cetuximab是否能促进体内RSL3诱导的铁死亡，研究人员建立了一个DLD-1异种移植裸鼠模型。所有小鼠在细胞移植或接受车载剂、RSL3、Cetuximab或两者联合治疗后都存活良好。然而，单独使用RSL3和同时使用RSL3和Cetuximab治疗均导致肿瘤大小和体积减小。与此同时，在与RSL3和Cetuximab联合处理后，Nrf2和HO-1相对水平降低，并且Keap1表达相对增加。[3]