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As patients with non-small cell lung cancer (NSCLC) and wild-type epidermal growth factor receptor (EGFR) are resistant to treatment with erlotinib or gefitinib, potential chemosensitizers are required to potentiate wild-type EGFR NSCLC cells to erlotinib/gefitinib treatment. The present study reported that shikonin could sensitize the anticancer activity of erlotinib/gefitinib in wild-type EGFR NSCLC cells. Furthermore, shikonin could potentiate mitochondrial-mediated apoptosis induced by erlotinib/gefitinib in wild-type EGFR NSCLC cells. In addition, the present study demonstrated that shikonin could induce apoptosis by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, and that erlotinib/gefitinib may also induce ER stress in wild-type EGFR NSCLC cells; however, shikonin plus erlotinib/gefitinib was more effective in activating ER stress than either agent alone. This indicated that ROS-mediated ER stress may be associated with enhanced mitochondrial apoptosis induced by shikonin plus erlotinib/gefitinib. In addition, shikonin may promote the transition of cytoprotective ER stress-inducing EGFR-tyrosine kinase inhibitor tolerance to apoptosis-promoting ER stress. Furthermore, shikonin may enhance the anti-NSCLC activity of erlotinib/gefitinib in vivo. The data of the present study indicated that shikonin may be a potential sensitizer to enhance the anti-cancer efficacy of erlotinib/gefitinib in wild-type EGFR NSCLC cells resistant to erlotinib/gefitinib treatment. [ABSTRACT FROM AUTHOR]

High-dose erlotinib is effective for non-small cell lung cancer patients with brain metastases. The aim of the present study was to investigate whether aspirin could increase the anti-proliferative and anti-metastatic effects of regular erlotinib treatment. The data demonstrated that combining aspirin with erlotinib significantly induced apoptosis and inhibited tumor cell proliferation in several human cancer types. Furthermore, aspirin plus erlotinib significantly induced the activation of E-cadherin and suppression of p38. The data also indicated that the p38/E-cadherin pathway may be involved in the apoptosis caused by the combination of aspirin and erlotinib. As p38 and E-cadherin also serve a key role in epithelial-to-mesenchymal transition (EMT) and cancer metastasis, we hypothesized that the combination of aspirin and erlotinib may significantly inhibit tumor metastasis. First, aspirin plus erlotinib achieved potent inhibition of cancer cell migration and invasion, which are crucial for cancer metastasis. Next, the results demonstrated that aspirin plus erlotinib inhibited angiogenesis by suppressing endothelial cell migration and invasion. Moreover, it was confirmed that aspirin plus erlotinib exerted synergistic anti-angiogenic effects. Finally, the synergistic anti-proliferative and anti-metastatic effects of the combination of aspirin with erlotinib were further validated in an A549 xenograft model in vivo. In conclusion, aspirin plus erlotinib may be an effective combination regimen for patients with metastatic cancer. [ABSTRACT FROM AUTHOR]

Regular use of aspirin after diagnosis is associated with longer survival among patients with mutated- PIK3 CA colorectal cancer, but not among patients with wild-type PIK3 CA cancer. In this study, we showed that clinically achievable concentrations of aspirin and ABT-737 in combination could induce a synergistic growth arrest in several human PIK3 CA wild-type cancer cells. In addition, our results also demonstrated that long-term combination treatment with aspirin and ABT-737 could synergistically induce apoptosis both in A549 and H1299 cells. In the meanwhile, short-term aspirin plus ABT-737 combination treatment induced a greater autophagic response than did either drug alone and the combination-induced autophagy switched from a cytoprotective signal to a death-promoting signal. Furthermore, we showed that p38 acted as a switch between two different types of cell death (autophagy and apoptosis) induced by aspirin plus ABT-737. Moreover, the increased anti-cancer efficacy of aspirin combined with ABT-737 was further validated in a human lung cancer A549 xenograft model. We hope that this synergy may contribute to failure of aspirin cancer therapy and ultimately lead to efficacious regimens for cancer therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Regorafenib has been approved to treat patients who have HCC progression after sorafenib failure, however, regorafenib also faces the risk of drug resistance and subsequent progression of HCC patients. As LSD1 inhibitors can alleviate acquired resistance to sorafenib, in this context, we are interested to investigate the role of LSD1 in regorafenib treatment. Firstly, over-expressed LSD1 was observed in HCC patients and predicted poor prognosis. However, regorafenib failed to suppress the expression of LSD1 in HCC cells. Thus, we hypothesized that LSD1 inhibition could enhance the anti-HCC activity of regorafenib. As expected, LSD1 knockdown could enhance anti-proliferation effect of regorafenib in HCC cells. LSD1 inhibitor SP2509 could enhance the cytotoxic and apoptotic effects of regorafenib in HCC cells. In addition, clinically used LSD1 inhibitor tranylcypromine also enhanced anti-HCC effect of regorafenib. Furthermore, LSD1 suppressed by SP2590 or tranylcypromine could alleviate the activated p -AKT (ser473) induced by regorafenib in HCC cells. Thus, inhibiting LSD1 might be an attractive target for regorafenib sensitization and clinical HCC therapy, our findings could help to elucidate more effective therapeutic options for HCC patients. Image 1 • Regorafenib fails to suppress the expression of LSD1 in HCC cells. • LSD1 knockdown enhances anti-HCC effects of regorafenib. • LSD1 inhibitors enhance anti-HCC effects of regorafenib. • LSD1 suppression alleviates the activated p -AKT (ser473) induced by regorafenib. • Suppressing LSD1 might be an attractive target for regorafenib sensitization. [ABSTRACT FROM AUTHOR]