The therapeutic potential of a novel non-ATP-competitive fibroblast growth factor receptor 1 inhibitor on gastric cancer

Abstract

Previous studies showed that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. In the current study, we aimed to investigate whether the compound L6123, a novel non-ATP-competitive FGFR1 inhibitor, could show better antitumor activity than the leading compound, nordihydroguaiaretic acid (NDGA), in FGFR1-overexpressing gastric cancer cells. Using an MTT assay, we investigated the inhibitory effect of L6123 on the viability of three gastric cancer cells (MGC-803, SGC-7901, and BGC-823) overexpressing FGFR1, wild-type mouse embryonic fibroblast (MEF), and MEF expressing FGFR1, FGFR2, and FRS2α gene knockout (MEF). We studied the antitumor mechanism of L6123 against the gastric cancer cell line SGC-7901 by western blot analysis. The antitumor effects of L6123 on the gastric cancer cell line SGC-7901 were detected by flow cytometry, Hoechst staining, western blot analysis, and Transwell invasion assay. L6123 had lower IC50 in all three gastric cancer cells than NDGA and showed better inhibitory activity against MEF cells than against MEF cells. In the SGC-7901 gastric cell, L6123 inhibited the FGF2-induced phosphorylation of FGFR1/FRS2α/ERK1/2 in a dose-dependent manner, induced the activation of the apoptosis-related proteins, cleaved-PARP and cleaved-caspase-3, decreased the expression of pro-caspase-3 and Bcl-2, and induced tumor cell apoptosis. L6123 also dose-dependently reduced cell invasion ability, and showed better activity than NDGA at the same concentration. A novel non-ATP-competitive inhibitor L6123 showed excellent antigastric cancer activity by inhibiting the FGFR1 signaling pathway. Thus, we discovered a potential agent for the treatment of FGFR1-overexpressing gastric cancer.

NDGA-P21, a novel derivative of nordihydroguaiaretic acid, inhibits glioma cell proliferation and stemness

“…Apoptosis has been suggested as one of the mechanisms underlying the inhibition of NDGA and its derivatives in multiple tumors. 4,16,17,35,36 However, we found that similar to Nordy, NDGA-P21 had little effects on apoptosis. The results suggest different structure modification of NDGA leads an alternative mechanism for inhibition of tumor cells.…”

“…NDGA is a natural product, which has been reported to inhibit growth of multiple tumors, such as breast cancer, cervical cancer, gastric cancer, lung cancer, prostate cancer, and neuroblastoma. [11][12][13][14][15][16][17][18] In previous studies, we found Nordy, as a synthetic chiral derivative of NDGA, repressed the growth of glioma cells both in vitro and in vivo. 7,[19][20][21] Figure 1), showed stronger inhibitory effects on the growth of GBM cells than Nordy.…”

Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect

“…Recently, selective inhibitors of the FGFRs have been developed and some of them are under phase study in patients with gastric cancer or advanced Gastrointestinal Stromal Tumor (GIST), such as AZD4547 (NCT01795768), JNJ-42756493 (NCT02699606) and BGJ398 (NCT02257541). Besides, our group also discovered some favorable FGFR1 inhibitors L16H50 (Wu et al, 2017a), L6123 (Xu et al, 2015), and Af23 (Wu et al, 2015), which exhibited effective anti-gastric cancer effects in vitro. These results suggested that FGFR1 may be a new target for the treatment of gastric cancer and FGFR1 inhibitors could be used as monotherapy or in combination with chemotherapy.…”

FGFR1 is an independent prognostic factor and can be regulated by miR-497 in gastric cancer progression

“…FGFR1 is implicated in the carcinogenesis of gastric cancer, and FGFR1 inhibitor, L16H50, and L6123 can suppress cell proliferation and migration in gastric cancer cells (6,29). In our study, shRNA was designed to inhibit FGFR1 expression by post-transcriptional gene silencing to explore the functions of FGFR1 in gastric cancer cell proliferation and apoptosis.…”