Trifolium Flavonoids Overcome Gefitinib Resistance of Non-Small-Cell Lung Cancer Cell by Suppressing ERK and STAT3 Signaling Pathways

Abstract

Gefitinib is a tyrosine kinase inhibitor of EGFR (epidermal growth factor receptor) and represents the first-line treatment for EGFR mutation patients with NSCLC (non-small-cell lung cancer) therapeutics. However, NSCLC patients are inclined to develop acquired gefitinib drug resistance through nowadays, unarticulated mechanisms of chemoresistance. Here, we investigated the role of TF (Trifolium flavonoids) on sensitizing gefitinib resistance in NSCLC cells and revealed its potential mechanism of action. We demonstrated that TF exerted significantly potential chemosensitivity in gefitinib resistant NSCLC cells. MTT assay and cytological methods were used to analyze cell viability and apoptosis in NSCLC cell line PC-9R. Both TF and gefitinib suppressed PC-9R cell growth in a dose-dependent manner. Subtoxic concentrations of TF did significantly augment gefitinib-induced apoptosis in PC-9R cell line. The TF promoted chemosensitivity was major mediated by the PARP and caspases activation. Meanwhile, the TF promoted chemosensitivity also decreased the expression of Bcl-2 and Mcl-1. Finally, TF significantly reduced the phosphorylation levels of STAT3 and ERK. Altogether, the results of the present study indicated the potential mechanisms of chemosensitivity of TF in gefitinib-induced apoptosis of NSCLC by downregulating ERK and STAT3 signaling pathways and Bcl2 and Mcl-1 expression and a promising application of TF in therapy of NSCLC with gefitinib resistant.

Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A

“…In addition, ERK and Akt signaling pathways are usually associated with proliferation and drug resistance of human cancer cells, including NSCLC cells. [41][42][43][44] Zeng et al reported that miR-222 inhibited the cisplatin sensitivity in bladder cancer cells via activation of Akt signaling by targeting PPP2R2A. 45 Consistent with previous studies, our data indicated that exosomal miR-136-5p promoted NSCLC cell proliferation and anlotinib resistance by targeting PPP2R2A and activation of Akt signaling pathway.…”

Perspectives on the Combined Effects of Ocimum basilicum and Trifolium pratense Extracts in Terms of Phytochemical Profile and Pharmacological Effects

“…Due to some common compounds the extracts from the plants T. pratense and O. basilicum have been shown to have similar therapeutic effects [ 34 , 35 , 36 ]. The biological activities specific to the T. Pratense and O. basilicum , but also its common biological effects are presented in Figure 3 [ 11 , 28 ].…”

Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles

“…Nevertheless, the chalcone xanthohumol attenuated the autophagy induced by imatinib, a small molecule TKI used to treat chronic myelogenous leukemia and enhanced its therapeutic efficacy in myelogenous leukemia K562 cells [111]. Further, Trifolium flavonoids showed a capacity to overcome resistance to gefitinib, EGFR-TKI, through suppressing ERK and STAT3 signaling in NSCLC cell line PC-9R [131]. A novel EGCG (flavonol) derivative isolated from Anhua dark tea sensitized NSCLC gefitinib-resistant cells HCC827-Gef to gefitinib through the suppression of PI3K/mTOR signalling and EMT [132].…”