Abstract
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. Approximately 15% of GC is associated with Epstein–Barr virus (EBV). GC is largely incurable with a dismal five-year survival rate. There is an urgent need to identify new therapeutic agents for the treatment of GC. Tenovin-6 was initially identified as a p53 activator, but it was later found to inhibit autophagy flux, and the protein deacetylase activity of sirtuins. Tenovin-6 shows promising therapeutic effect in various malignancies. However, it remains unknown whether Tenovin-6 is effective for GC. In this study, we found that EBV-positive and -negative GC cell lines were sensitive to Tenovin-6 but with different response times and doses. Tenovin-6 suppressed anchorage-independent growth of GC cells. Tenovin-6 induced different levels of apoptosis and phases of cell-cycle arrest depending on the cell lines with some manifesting gap 1 (G1) and others showing synthesis (S) phase cell-cycle arrest. Mechanistically, Tenovin-6 induced autophagy or p53 activation in GC cells depending on the status of TP53 gene. However, initiation of autophagy following treatment with Tenovin-6 conferred some protective effect on numerous cells. Combined treatment with Tenovin-6 and autophagy inhibitor chloroquine increased the cytotoxic effect by inducing microtubule-associated protein 1 light chain 3B (LC3B)-II accumulation, and by enhancing apoptosis and cell-cycle arrest. These results indicated that Tenovin-6 can be used as a potential therapeutic agent for GC, but the genetic background of the cancer cells might determine the response and mechanism of action. Treatment with Tenovin-6 alone or in combination with chloroquine could be a promising therapeutic approach for GC.
Highlights
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death
To determine whether the enhanced cytotoxic effect of Tenovin-6 by chloroquine was due to the inhibitory effect of chloroquine on autophagy flux, we examined light chain 3B (LC3B)-II and p62 protein levels
Tenovin-6 alone showed a promising anti-neoplastic effect in vitro or in vivo on various malignancies [6,7,8,11,12,13,53,54,55,56]; secondly, Tenovin-6 seems to be safe in mice, since no obvious adverse effect is reported so far [6,53,55,56,57]; thirdly, our results showed that Tenovin-6 initiated autophagy, which conferred a protective effect, in numerous cell lines; fourthly, this study demonstrated that combined treatment with Tenovin-6 and chloroquine enhanced the cytotoxicity and synergistically induced apoptosis and gap 1 (G1) cell-cycle arrest in different GC cell lines compared to the treatment with either inhibitor alone (Figures 4 and 5)
Summary
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. In 2018, there were 1,000,000 new cases and an estimated 783,000 deaths of GC [1]. 15% of GC is associated with Epstein–Barr virus (EBV) [2]. Gastric cancer remains asymptomatic and lacks effective biomarkers for detection. Most gastric cancer cases are diagnosed with distant metastasis at an advanced stage [3]. Advanced GC is largely incurable with a dismal five-year survival rate. Cisplatin and 5-fluorouracil remain the mainstay of treatment for people with advanced GC, both of which have high side effects [4]. There is an urgent need to explore new therapeutic agents for the treatment of GC
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