DHW-221, a Dual PI3K/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer

Abstract

Multidrug resistance (MDR) is considered as a primary hindrance for paclitaxel failure in non-small cell lung cancer (NSCLC) patients, in which P-glycoprotein (P-gp) is overexpressed and the PI3K/Akt signaling pathway is dysregulated. Previously, we designed and synthesized DHW-221, a dual PI3K/mTOR inhibitor, which exerts a remarkable antitumor potency in NSCLC cells, but its effects and underlying mechanisms in resistant NSCLC cells remain unknown. Here, we reported for the first time that DHW-221 had favorable antiproliferative activity and suppressed cell migration and invasion in A549/Taxol cells in vitro and in vivo. Importantly, DHW-221 acted as a P-gp inhibitor via binding to P-gp, which resulted in decreased P-gp expression and function. A mechanistic study revealed that the DHW-221-induced FOXO3a nuclear translocation via Akt inhibition was involved in mitochondrial apoptosis and G0/G1 cell cycle arrest only in A549/Taxol cells and not in A549 cells. Interestingly, we observed that high-concentration DHW-221 reinforced the pro-paraptotic effect via stimulating endoplasmic reticulum (ER) stress and the mitogen-activated protein kinase (MAPK) pathway. Additionally, intragastrically administrated DHW-221 generated superior potency without obvious toxicity via FOXO3a nuclear translocation in an orthotopic A549/Taxol tumor mouse model. In conclusion, these results demonstrated that DHW-221, as a novel P-gp inhibitor, represents a prospective therapeutic candidate to overcome MDR in Taxol-resistant NSCLC treatment.

ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

“…Similarly, dactolisib reversed drug resistance mediated by ABCB1 and ABCG2 in AML [ 77 ] and mesothelioma cell lines [ 78 ], respectively. Others such as perifosine [ 79 ], BEZ235 [ 80 ], and DHW-211 [ 81 ] have been reported to reverse drug resistance in ABCB1-overexpressing breast cancer, ovarian cancer, and NSCLC cell lines, respectively. We found that although HS-173 could inhibit ABCB1-mediated efflux of calcein-AM and ABCG2-mediated PhA efflux at higher concentrations ( Figure 5 ), HS-173 was unable to reverse the drug resistance mediated by ABCB1 or ABCG2 at sub-toxic concentrations ( Table 3 ).…”

Mechanism of multidrug resistance to chemotherapy mediated by P‑glycoprotein (Review)

“…The sensitivity of adrenocortical carcinoma to mitotane, DOX, etoposide, cisplatin and streptozotocin can be significantly enhanced by verapamil and tariquidar, which are known as competitive P-gp inhibitors and nontransporter P-gp inhibitors ( 78 ). DHW-221, a dual PI3K/mTOR inhibitor, has also been found to bind P-gp to competitively inhibit efflux function and downregulate P-gp ( 15 ). The triazolo[1,5-a]pyrimidine derivative WS-716 ( 79 ), some 1,4-substituted arylalkyl piperazine derivatives ( 80 ), pyrimidine aminobenzene derivatives ( 81 ), 5-phenylfuran derivatives characterized by alkyl-substituted phenols and 6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline ( 82 ), and the 4-indolyl quinazoline derivative YS-370 ( 83 ) have been reported to be potential P-gp competitive inhibitors.…”

“…TMDs consist of six transmembrane α-helical structures that provide specificity for substrates. Chemotherapy drugs that act as P-gp substrates are pumped out of tumor cells ( 14 , 15 ).…”

Discovery of novel and potent tacrine derivatives as CDK2 inhibitors

“…The cell cycle Assay was performed according to a previous standard protocol. 24 The SW480 cells were treated with indicated concentrations of compound ZLHT-7 (0 μM, 1 μM, 2 μM and 4 μM) for 48 h with DMSO as a vehicle. Then, the cells were harvested, washed three times with PBS, and fixed with 70% cold ethanol overnight.…”