Dihydroartemisinin enhances the sensitivity of gefitinib in non-small cell lung cancer cells by inhibiting STAT3

Abstract

Lung cancer is the most frequent cause of cancer death, and non-small cell lung cancer (NSCLC) is the most common subtype. EGFR (epidermal growth factor receptor) mutations are found in about 50% of Asian patients with lung adenocarcinoma and confer sensitivity to EGFR tyrosine kinase inhibitor (EGFR-TKI). Progression free survival with TKI treatment is 9 to 12 months, and median survival time is about 20–30 months. However, acquired resistance to TKI unfailingly occurs, in most cases due to the acquisition of secondary mutations in the EGFR . Many studies have shown that bypass pathway activation ( c-MET or Her-2 amplification) and the activation of the downstream pathways (PI3K/AKT, PTEN, ERK/MAPK, STAT3) can lead to acquired resistance to EGFR-TKI. In addition, transformation from NSCLC to SCLC or conferred epithelial to mesenchymal transition has also been identified as mechanisms of acquired resistance to EGFR-TKI. The need to overcome both innate and acquired resistance has been a major therapeutic challenge. Our research group aim to explore the natural compounds or their derivatives which can overcome the acquired resistance to EGFR-TKI from the library of traditional Chinese medicine monomer and related derivatives. Fortunately, we found that dihydroartemisinin (DHA) had a synergistic inhibition effect with gefitinib (first-generation EGFR-TKI) in non-small cell lung cancer cells. The combined index (CI) was 0.751 in gefitinib-sensitive cell line PC-9 cells and 0.766 in gefitinib-resistant cell line H1975 cells, respectively. DHA is a semi-synthetic derivative and main active metabolite of the artemisinin, a natural product isolated from a Chinese medicinal herb ( Artemisia annua Linn.). It is one of first-line antimalarial drugs. Moreover, DHA has been shown to exert antibacterial, antiviral and therapeutic effects on lupus erythematosus. In addition to these efficacies, evidence from epidemiological, pharmacological and case control studies has suggested that DHA possesses antitumor activity and selective cytotoxicity to various malignancies. Notably, its low toxicity to host is the major incentive for developing the compound as an anticancer agent. Our present study also investigated the mechanisms by which DHA repressed cell growth in NSCLC cells, alone or in combination with EGFR-TKI. We found that DHA could inhibit phosphorylation of STAT3 (Tyr705) in non-small cell lung cancer cells. When combined with gefitinib, DHA also could inhibit gefitinib-activated STAT3 and does not affect its TKI activity. Many studies have shown that STAT3 is persistently tyrosine-phosphorylated or activated in NSCLC (cell lines and primary tumors), leading to acquired resistance to EGFR-TKI. In summary, DHA can be used to overcome acquired resistance to TKIs in EGFR-mutant lung adenocarcinoma due to its STAT3 inhibitory activity and low toxicity.