Abstract
Homoharringtonine (HHT), an inhibitor of protein synthesis, has been used to treat leukemia. Its therapeutic effects on non-small cell lung adenocarcinoma carrying KRAS mutation and their immune system are less understood. The present study examined the therapeutic efficacy and the immune effects of HHT in two murine lung tumor models, xenograft and transgenic, carrying the Kras mutation G12D and G12C respectively. HHT exhibited efficient anticancer activity, significantly suppressing lung tumor growth in vitro and in vivo. The levels of 22 cytokines and chemokines in splenocytes of tumor-bearing mice were examined. Interleukin-12 expression was lower in splenocytes of HHT-treated mice when compared to the controls as demonstrated by a cytokine array and an enzyme-linked immunosorbent assay. The expression levels of CD80, CD86, and CD69 in B220+ B cells from splenocytes of HHT-treated mice were higher than that of control mice in two mouse tumor models. Furthermore, antitumor effect of HHT was attenuated with depletion of B cells. Increased numbers of CD80+ and CD86+ B cells were observed in the mice treated with narciclasine, another translation inhibitor. In conclusion, HHT changed the features of immune cells, and exhibited efficient anti-tumor activity against lung tumor carrying mutant Kras expression.
Highlights
Indicated that NSCLC patients with KRAS mutations were resistant to EGFR-targeted treatments, including monoclonal antibodies and tyrosine kinase inhibitors[8,9]
Combination of high dose of recombinant IL-12 (0.5 μg) and HHT increased the cancer therapy effects (Fig. S3D). These results suggested that decrease of IL-12 may be responsible for the increase of B220+ CD86+ B cells during HHT treatment (Figs 2 and 3)
KRAS mutations are common in various types of cancer, and it has been studied as a drug target for many years
Summary
Indicated that NSCLC patients with KRAS mutations were resistant to EGFR-targeted treatments, including monoclonal antibodies and tyrosine kinase inhibitors[8,9]. Various clinical studies demonstrated that HHT elicited the anti-tumor activity in AML and CML, either alone or in combination with interferon-α (IFN-α) or granulocyte colony-stimulating factor[23,24]. In a gefitinib-resistant NSCLC model, HHT induced anti-tumor effects by suppressing interleukin-6 (IL-6)/JAK1/ STAT3 signaling[31]. The effects of protein translation inhibitor on the cytokine production in tumor microenvironment have not been studied yet. The present study investigated anti-tumor activity and changes in cytokine production induced by translation inhibitor, HHT, in mouse models carrying the Kras mutation. The results revealed that HHT exhibited effective anti-cancer activity in lung cancer mouse models of NSCLC and that it reduced IL-12 cytokine expression and enhanced B-cell activation
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