Dihydroartemisinin and gefitinib synergistically inhibit NSCLC cell growth and promote apoptosis via the Akt/mTOR/STAT3 pathway

Abstract

Non‑small cell lung cancer (NSCLC) is among the leading causes of cancer‑associated mortality worldwide. In clinical practice, therapeutic strategies based on drug combinations are often used for the treatment of various types of cancer. The present study aimed to investigate the effects of the combination of dihydroartemisinin (DHA) and gefitinib on NSCLC. Cell Counting kit 8 assay was used to evaluate cell viability. Transwell assays were performed to investigate cellular migration and invasion, and cellular apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick‑end labeling assay. Flow cytometry was used to investigate cell cycle distribution and the expression levels of target proteins were determined using western blot analysis. The results of the present study demonstrated that DHA (5, 10, 20, 50 and 100 µM) reduced cancer cell viability in a dose‑dependent manner in the NCI‑H1975 human NSCLC cell line and significantly enhanced gefitinib‑induced apoptosis. Furthermore, DHA and gefitinib co‑administration induced cell cycle arrest in G2/M phase, which was associated with a marked decline in the protein expression levels of G2/M regulatory proteins, including cyclin B1 and cyclin‑dependent kinase 1. The addition of DHA appeared to potentiate the inhibitory actions of gefitinib on the migratory and invasive capabilities of NCI‑H1975 cells. DHA and gefitinib co‑administration also downregulated the expression levels of phosphorylated (p)‑Akt, p‑mechanistic target of rapamycin, p‑signal transducer and activator of transcription 3 and B‑cell lymphoma 2 (Bcl‑2), and upregulated the expression of Bcl‑2‑associated X protein. In conclusion, the present results suggested that the combination of DHA and gefitinib may have potential as a novel and more effective therapeutic strategy for the treatment of patients with NSCLC.

lncRNA DLEU1 contributes to tumorigenesis and development of endometrial carcinoma by targeting mTOR

“…[34][35][36] In addition, in non-small cell lung cancer, cervical cancer, and breast cancer, STAT3 expression is consistent with PI3K/Akt/mTOR pathway and promotes cell proliferation and tumorigenicity. [37][38][39] Moreover, in mantle cell lymphoma, Bcl-xl expression was also inhibited after inhibition of BTK and mTOR simultaneously. 40 Accordingly, we hypothesized that the carcinogenic effect of lncRNA DLEU1 may be achieved by acting on mTOR and then improving the effects of PI3K/AKT/mTOR pathway and relative molecules.…”

“…Recent studies have proposed that GSK3β is a downstream molecule of PI3K/Akt/mTOR pathway, which has been demonstrated to be associated with cancer‐promoting effect in osteosarcoma, serous endometrial cancer, and cancerous sarcoma . In addition, in non‐small cell lung cancer, cervical cancer, and breast cancer, STAT3 expression is consistent with PI3K/Akt/mTOR pathway and promotes cell proliferation and tumorigenicity . Moreover, in mantle cell lymphoma, Bcl‐xl expression was also inhibited after inhibition of BTK and mTOR simultaneously .…”

Dihydroartemisinin Sensitizes Mutant p53 (R248Q)-Expressing Hepatocellular Carcinoma Cells to Doxorubicin by Inhibiting P-gp Expression

“…DHA exhibits cytotoxic effects at higher concentration but has little cytotoxic effect at lower concentration on cancer cells [24]. To study the synergistic effect of DHA with ADM, we must screen proper concentration of DHA which has little cytotoxic effect on Hep3B cells.…”

“…Cells. Since the combination of DHA with chemotherapeutic agents exerts synergistic effects in the treatment of many kinds of cancers [24,25], we next explored whether DHA could enhance the sensitivity to ADM in p53 (R248Q)-expressing HCC cells. e chemical structure of DHA was shown in Figure 2(a) [26].…”

“…Meanwhile, DHA induces apoptosis in human HCC cells harboring p53-null, wild-type (WT) p53, and mutant p53, respectively [23]. Furthermore, the combination of DHA and other chemotherapeutic agents plays a synergistic role in the treatment of many kinds of cancers [24,25]. However, whether DHA could enhance the sensitivity of p53 (R248Q)-expressing HCC cells to ADM and the underlying mechanism remains unknown.…”