A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress.

BACKGROUND: NSCLC is the major type of lung cancer and the survival rates of NSCLC patients remain low. AZD9291 is a third-generation EGFR-TKI and approved to treat NSCLC patients harboring EGFR T790M mutation and common targetable activating EGFR mutations, but it has a limited effect for wtEGFR NSCLC. PURPOSE: The current study investigated whether shikonin could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. METHODS: SRB and colony formation assay were used to detect the proliferation of NSCLC cells, propidium iodide staining was performed to detect the apoptosis, ROS was analyzed using DCFH-DA staining, and western blot was used to detect the expression of indicated proteins. RESULTS: We demonstrated that shikonin, a natural ROS inducer, could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. In addition, shikonin increased AZD9291-induced apoptosis accompanying with the generation of ROS and activation of ER stress. Furthermore, ROS inhibition by NAC or GSH reversed the apoptosis induced by shikonin plus AZD9291, and recovered the ER stress activated by combination treatment, indicating that ROS mediated ER stress played a vital role in this combination therapy. Moreover, shikonin increased the anticancer activity of AZD9291 in primary wtEGFR NSCLC cells through ROS-mediated ER stress. CONCLUSION: Our study suggests that combining shikonin with AZD9291 is a promising therapeutic strategy for treating wtEGFR NSCLC patients.

BAY 87-2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK-3ß activation.

Hepatocellular carcinoma (HCC) is associated with some of the highest cancer-associated mortality rates. Histone deacetylase (HDAC) inhibitors anti-HCC activities have been shown to promote Snail-induced metastasis. In the present study, it was shown that BAY 87-2243, a hypoxia-inducible transcription factor-1α inhibitor, could enhance the anti-HCC effects of HDAC inhibitors, including trichostatin A and vorinostat. In addition, BAY 87-2243 plus HDAC inhibitors exhibited synergistic cytotoxicity and induced significant cell death in Hep3B cells. Additionally, BAY 87-2243 combined with HDAC inhibitors-treated Hep3B cells formed fewer and smaller colonies as compared with either the control or single agent-treated cells. Furthermore, glycogen synthase kinase-3ß might be involved in the enhanced cell death induced by BAY 87-2243 plus HDAC inhibitors. The present data also indicated that BAY 87-2243 combined with HDAC inhibitors could suppress the migration of Hep3B cells, and BAY 87-2243 could reverse the HDAC inhibitor-induced Snail activation in Hep3B cells. In conclusion, BAY 87-2243 combined with HDAC inhibitors might be an attractive chemotherapy strategy for HCC therapy.