Dual effects of the PI3K inhibitor ZSTK474 on multidrug efflux pumps in resistant cancer cells

Abstract

ZSTK474 is a potent phosphoinositide 3-kinase (PI3K) inhibitor that reduces cell proliferation via G-arrest. However, there is little information on the susceptibility of this anticancer drug to resistance conferred by the multidrug pumps P-glycoprotein (ABCB1) and ABCG2. We have demonstrated that ZSTK474 generated cytotoxicity in cells over-expressing either pump with potency similar to that in drug sensitive cells. In addition, the co-administration of ZSTK474 with the cytotoxic anti-cancer drugs vinblastine and mitoxantrone caused a potentiated cytotoxic effect in both drug sensitive and efflux pump expressing cells. These observations suggest that ZSTK474 is unaffected by the presence of multidrug efflux pumps and may circumvent their activities. Indeed, ZSTK474 increased the cellular accumulation of calcein-AM and mitoxantrone in cells expressing ABCB1 and ABCG2, respectively. ZSTK474 treatment also resulted in reduced expression of both efflux pumps in multidrug resistant cancer cells. Measurement of ABCB1 or ABCG2 mRNA levels demonstrated that the reduction was not due to altered transcription. Similarly, inhibitor studies showed that the proteasomal degradation pathway for ABCB1 and the lysosomal route for ABCG2 degradation were unaffected by ZSTK474. Thus the mechanism underlying reduced ABCB1 and ABCG2 levels caused by ZSTK474 was due to a reduction in overall protein synthesis; a process influenced by the PI3K pathway. In summary, ZSTK474 is not susceptible to efflux by the resistance mediators ABCB1 and ABCG2. Moreover, it inhibits the drug transport function of the pumps and leads to a reduction in their cellular expression levels. Our observations demonstrate that ZSTK474 is a powerful anticancer drug.

Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines

“…In addition, the reversal effect of PI3K/AKT signaling pathway inhibitors on MDR mediated by ABCB1 and/or ABCG2 in cancer cells has also been described. It was reported that through the inhibition of the PI3K/AKT signaling pathway, ZSTK474 inhibited the drug transport function and downregulated the protein expression of ABCB1 and ABCG2 [92], whereas PI103 [93], perifosine [94], and LY294002 [95] downregulated ABCB1 expression in sarcoma, breast cancer, and gastric cancer cells, respectively. The PI3K/mTOR dual inhibitor dactolisib reversed MDR mediated by ABCB1 and ABCG2 in multidrug-resistant acute myeloid leukemia (AML) cells [96] and mesothelioma cell lines [97], respectively.…”

Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents

“…The calcein-AM assay to measure the transport function of P-gp was based on previously published methods. , MCF-7 WT and NCI/Adr RES cells were seeded into 96-well tissue-culture plates at a density of 2 × 10 3 cells per well in 100 μL and allowed to adhere for 2 days at 37 °C with 5% CO 2 . Following incubation, the medium was aspirated and cells were washed with PBS and resuspended in 100 μL Hank’s buffered salt solution (HBSS).…”

Exploring synthetic lethal network for the precision treatment of clear cell renal cell carcinoma

“…In vitro experiments have shown that it can inhibit the proliferation of tumor cells through interfering cell G0/1 stage arrest 42 , 43 . It is exciting that ZSTK474 induced the degradation of multidrug efflux pumps ABCB1 and ABCG2 so as not to be affected by the efflux effect of resistant cancer cells 44 . Furthermore, ZSTK474 exhibited antiangiogenic activity via downregulating HIF-1α and VEGF, and suppressed renal cancer growth in a xenograft model 45 .…”