The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

Modulation of the redox system in cancer cells has been considered a promising target for anti-cancer therapy. The novel MTH1 inhibitor TH588 proved tremendous potential in terms of cancer cell eradication, yet its specificity has been questioned by recent reports, indicating that TH588 may also induce cancer cell death by alternative mechanisms than MTH1 inhibition. Here we used a panel of heterogeneous neuroendocrine tumor cells in order to assess cellular mechanisms and molecular signaling pathways implicated in the effects of TH588 alone as well as dual-targeting approaches combining TH588 with everolimus, cytotoxic 5-fluorouracil or γ-irradiation. Our results reflect that TH588 alone efficiently decreased the survival of neuroendocrine cancer cells by PI3K-Akt-mTOR axis downregulation, increased apoptosis and oxidative stress. However, in the dual-targeting approaches cell survival was further decreased due to an even stronger downregulation of the PI3K-Akt-mTOR axis and augmentation of apoptosis but not oxidative stress. Furthermore, we could attribute TH588 chemo- and radio-sensitizing properties. Collectively our data not only provide insights into how TH588 exactly kills cancer cells but also depict novel perspectives for combinatorial treatment approaches encompassing TH588.

癌细胞氧化还原系统的调控，已被视为抗癌治疗的极具前景的靶点。新型MTH1抑制剂（MTH1 inhibitor）TH588在根除癌细胞方面展现出巨大潜力，但近期研究对其特异性提出了质疑，表明TH588或可通过不依赖MTH1抑制的其他机制诱导癌细胞死亡。本研究采用一组异质性神经内分泌肿瘤细胞系，以评估TH588单药治疗，以及TH588联合依维莫司（everolimus）、细胞毒性药物5-氟尿嘧啶（5-fluorouracil）或γ射线照射（γ-irradiation）的双靶向治疗策略所涉及的细胞机制与分子信号通路。研究结果显示，TH588单药可通过下调PI3K-Akt-mTOR信号轴（PI3K-Akt-mTOR axis）、诱导细胞凋亡与氧化应激，有效降低神经内分泌癌细胞的存活率。然而在双靶向治疗策略中，由于PI3K-Akt-mTOR信号轴的下调程度进一步增强，且细胞凋亡水平升高（但氧化应激未受显著影响），癌细胞存活率进一步降低。此外，本研究证实了TH588的化学增敏与放射增敏特性。综上，本研究数据不仅阐明了TH588杀伤癌细胞的确切机制，还为包含TH588的联合治疗方案提供了全新的研究视角。