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A new thiadiazine derivative induces oxidative stress dependent JNK pathway activation and cell death in hepatocellular carcinoma

Kahraman, Deniz Cansen
Atalay, Rengül
Hepatocellular carcinoma (HCC) is the fifth most common and the second lethal cancer worldwide. HCC is resistant to conventional chemotherapy and radiotherapy due to its highly heterogenous structure. Therefore, it is crucial to design and develop novel therapeutic strategies against HCC. Non-steroidal anti-inflammatory drugs (NSAIDs) have long been studied for the treatment of acute and chronic conditions with pain and inflammation. In recent years, evidence from various studies suggested that NSAIDs reduce the incidence and mortality of various types of cancers. Here, investigated the possible cytotoxic bioactivities of a series of triazolothiadiazine derivatives on HCC cells, which have been previously reported as potent analgesic/anti-inflammatory compounds. For this purpose, we first investigated the anticancer effect of our compounds bearing a triazolothiadiazine core. Initially, 30 compounds were tested against cancer cells. Among all the compounds, three of them (7a, 7b and 7c) showed noticeable cytotoxic activities within µM concentrations and were selected to be screened against a panel of HCC cell lines. Compound 7b was identified as a promising anti-cancer agent against liver cancer cells with cytotoxic doses (less than 5µM) assessed by both the SRB assay and RT-CES analysis and was analyzed with further in vitro and in vivo experiments to disclose the underlying mechanism of its action in HCC cells. Time- and dose- dependent growth inhibition upon treatment with compound 7b was observed due to cell cycle arrest at the G2/M phase and apoptosis. After detecting the activation of SAPK/JNK pathway, it was shown that ROS accumulation was triggering the downstream events and eventually apoptotic cell death. Furthermore, upon treatment with compound 7b, overall survival of xenografts increased, while the tumor size decreased compared to control groups. Additionally, we investigated the potential of this compound on liver cancer stem cell population (CD133+/EpCAM+) which are known to be responsible for drug resistance in HCC. Compound 7b was bioactive against LCSCs and decreased the ratio of CD133+/EpCAM+ population significantly in both Huh7 and Mahlavu cells. Altogether, the anti-tumor and anti-resistance effects of compound 7b approves that this small molecule can be considered as an anti-cancer agent for liver cancer therapeutics.