Dataset Information

WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines.

ABSTRACT: Multidrug resistance (MDR) is a major reason for the failure of acute myeloid leukemia (AML) therapy. Agents that reverse MDR and sensitize AML cells to chemotherapy are of great clinical significance. The present study developed Adriamycin (Adr)?resistant cell lines, namely K562/Adr200 and K562/Adr500, which exhibited MDR. The upregulation of ATP?binding cassette subfamily B member 1 (ABCB1) was confirmed as the mechanism of resistance by reverse transcription?quantitative polymerase chain reaction and western blot analyses. Subsequently, the role of the mammalian target of rapamycin (mTOR) kinase inhibitor, WYE?354, in sensitizing the K562/Adr200 and K562/Adr500 cell lines to Adr was evaluated. At sub?cytotoxic concentrations, WYE?354 increased Adr cytotoxicity in the K562/Adr200 and K562/Adr500 cells. WYE?354 restored Adr sensitivity in the resistant cells by inhibiting ABCB1?mediated substrate efflux, thereby leading to an accumulation of Adr, an increase in Adr?mediated G2/M cell cycle arrest and the induction of apoptosis. Furthermore, WYE?354 stimulated the ATPase activity of ABCB1, which was consistent with in silico predictions using a human ABCB1 mouse homology model, indicating that WYE?354 is a potent substrate of ABCB1. WYE?354 did not regulate the expression of ABCB1 at the concentrations used in the present study. These findings indicate that WYE?354 may be a competitive inhibitor of ABCB1?mediated efflux and a potential candidate in combination with standard chemotherapy for overcoming MDR. Further clinical investigations are warranted to validate this combination in vivo.

SUBMITTER: Ibrahim SM

PROVIDER: S-EPMC6489006 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines.

Ibrahim Sara M SM Bakhashab Sherin S Ilyas Asad M AM Pushparaj Peter N PN Karim Sajjad S Khan Jalaluddin A JA Abuzenadah Adel M AM Chaudhary Adeel G AG Al-Qahtani Muhammed H MH Ahmed Farid F

Oncology reports 20190402 6

Multidrug resistance (MDR) is a major reason for the failure of acute myeloid leukemia (AML) therapy. Agents that reverse MDR and sensitize AML cells to chemotherapy are of great clinical significance. The present study developed Adriamycin (Adr)‑resistant cell lines, namely K562/Adr200 and K562/Adr500, which exhibited MDR. The upregulation of ATP‑binding cassette subfamily B member 1 (ABCB1) was confirmed as the mechanism of resistance by reverse transcription‑quantitative polymerase chain reac ...[more]

PMID: 30942458

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Project description:The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer.

Dataset Information

WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines.

Publications

WYE-354 restores Adriamycin sensitivity in multidrug-resistant acute myeloid leukemia cell lines.

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