The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer

Abstract

Background : The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is hyperactivated in lung cancer and regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. Thus PI3K is considered a promising target for therapy. To date, PI3K inhibitors have not been approved for lung cancer. Recent studies showed that the antipsychotic agent flupentixol induced apoptosis of lung cancer cell, however the anti-tumor mechanism of flupentixol remains unclear. Methods : (1) The idock software simulated the molecular docking between the PI3Kα protein and flupentixol. (2) Inhibition of PI3Kα by the flupentixol was examined by in vitro kinase assays. (3) The cytotoxicity of flupentixol on the NSCLC cell lines was tested by MTT assays. (4) We treated A549 and H661 cells with flupentixol and then measured the percentage of apoptotic cells by the Annexin V/PI analysis. (5) We investigated the effect of flupentixol on the expression of critical PI3K/AKT signaling pathway proteins, further analyzed on the cleavage of PARP and caspase-3 by Western blotting. (6) BALB/C nude mice were subcutaneously injected with A549 cells to evaluate the effect of flupentixol on the growth of lung carcinoma. Results : Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3Kα. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kα kinase activity. Flupentixol exhibited cytotoxicity in lung cancer cell lines A549 and H661 in a dose- and time-dependent manner. Furthermore, flupentixol more strongly inhibited the phosphorylation of AKT (T308 and S473) and the expression of its downstream target gene Bcl-2 than two known PI3K inhibitors (BYL719 and BKM120). Flupentixol induced apoptosis as measured by PARP and caspase-3 cleavage. Finally, flupentixol significantly suppressed A549 xenograft growth in BALB/C nude mice. Conclusions : Flupentixol could be docked to the PI3Kα protein and specifically inhibit the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo . As an old drug, flupentixol is a new PI3K inhibitor that may be used for the treatment of lung cancers.

iGlioSub: an integrative transcriptomic and epigenomic classifier for glioblastoma molecular subtypes

“…Flupentixol, an antipsychotic drug used by schizophrenia patients, diminishes genes related to G1/S and G2/M transition, specifically upregulated in the Proneural subtype. Furthermore, this drug has been proposed as a novel anticancer therapy in lung cancer [ 45 ].…”

Plantamajoside modulates the proliferation, stemness, and apoptosis of lung carcinoma via restraining p38MAPK and AKT phosphorylation

“…AKT and p38 MAPK-induced apoptosis has usually been observed in antitumor therapeutics. Flupentixol, for instance, could be specifically docked to PI3K to inhibit the PI3K/AKT pathway and survival of lung cancer cells ( 27 ). Meanwhile, torilis japonica extract induced apoptosis by reducing the mitochondrial membrane potential via the regulation of the AMPK-p38 MAPK signaling pathway ( 28 ), and Paris Saponin I enhanced apoptosis by influencing the p38 MAPK, ERK, and Akt pathways in lung cancer cells ( 4 ).…”

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

“…previous study showed that the inhibition of PI3K by econazole significantly sensitized MDA-MB-231 and MCF-7 cells to adriamycin in vitro and in vivo (Dong et al, 2020). In addition, the pan-PI3K inhibitor BKM120 showed a potent antitumor ability in both sensitive and MDR breast cancer cells by inhibiting the PI3K/AKT/NF-κB signaling pathway, and the combination of BKM120 with doxorubicin showed a synergistic effect (Hu et al, 2015).…”