Abstract 2321: Reactive oxygen species dictate the apoptotic response of melanoma cells to TH588

Abstract

Abstract Cancer cells commonly contain elevated levels of reactive oxygen species (ROS) resulting from oncogenic stimulation. On one hand, ROS promote cancer cell survival, proliferation, and metastasis. On the other, high levels of ROS suppress tumour growth through inhibition of proliferation and induction of apoptosis and senescence via damage to DNA. Incorporation of oxidized dNTPs such as 8-oxo-deoxy-guanine (8-oxo-dGTP) and 2-OH-deoxy-adenosine (2-OH-dATP) into genomic DNA plays an important role in apoptosis induced by ROS. Human MutT homolog 1(MTH1) is an enzyme that sanitizes oxidized dNTP pools through converting 8-oxo-dGTP and 2-OH-dATP into monophosphates, thus preventing their incorporation into genomic DNA. Inhibition of MTH1 by small molecule inhibitors has been suggested to be a promising approach in cancer treatment. However, we have found that while silencing of MTH1 does not affect survival of melanoma cell, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homologue of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a ROS scavenger or an antioxidant attenuated apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of ROS. Collectively, these results suggest that: 1) TH588-induced apoptosis of melanoma cells is not associated with its inhibitory effect on MTH1; 2) TH588 remains a promising candidate for the treatment of melanoma; 3) MTH1 inhibition in combination with oxidative stress inducers may be a useful approach in melanoma treatment; and 4) the endogenous levels of ROS are a potential biomarker for prediction of the response of melanomas to TH588 and MTH1 inhibition in combination with oxidative stress inducers. Citation Format: jiayu wang, Jin Lei, Xu Guang yan, Simonne Sherwin, Margaret Farrelly, Yuan Yuan Zhang, Fen Liu, Chun Yan Wang, Su Tang Guo, Hamed Yari, Ting La, Jennifer McFarlane, Fu Xi Lei, Hessam Tabatabaee, Jie Zhong chen, Amanda Croft, chen chen Jiang, Xu Dong Zhang. Reactive oxygen species dictate the apoptotic response of melanoma cells to TH588 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2017-2321