Glucose transporter‑1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells

Shima, Takafumi; Taniguchi, Kohei; Tokumaru, Yoshihisa; Inomata, Yosuke; Arima, J; Lee, Sang‐Woong; Takabe, Kazuaki; Yoshida, Kazuhiro; Uchiyama, Kazuhisa

doi:10.3892/or.2021.8218

Cited by 19 publications

(24 citation statements)

References 56 publications

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“…Inhibiting glucose uptake by small molecules has been considered a promising target for cancer therapy. WZB117 reduces intracellular glucose levels by inhibiting GLUT1 function and has anti-tumor effects on various malignant cells (Liu et al, 2012;Li et al, 2019;Peng et al, 2019;Shima et al, 2022). Similar to previous studies, we found that WZB117 effectively inhibited the proliferation of melanoma cells.…”

supporting

confidence: 89%

“…Glucose transporter 1 (GLUT 1), a rate-limiting factor of glucose transport in tumor cells, is frequently upregulated in multiple solid tumors and associated with more aggressive phenotypes and poor survival (Fu et al, 2016;Wang et al, 2017). WZB117 is a synthetic small molecule GLUT1 inhibitor, which has been shown to have anticancer activity against multiple solid tumors, providing a promising option for further development of anticancer therapies (Liu et al, 2012;Li et al, 2019;Shima et al, 2022). However, the antitumor effects of WZB117 on melanoma remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis

Zhang

Li²,

Liu³

et al. 2022

Front. Pharmacol.

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Background: Melanoma is the most lethal skin malignant tumor with a short survival once stepping into the metastatic status and poses a therapeutic challenge. Apatinib (a tyrosine kinase inhibitor) is a promising antiangiogenic agent for the treatment of metastatic melanoma. However, antiangiogenic monotherapy is prone to acquired drug resistance and has a limited therapeutic effect. The persistence dependence of glycolytic metabolism in antiangiogenic therapy-resistant cells provides evidence that glycolysis inhibitors may enhance the effect of antiangiogenic therapy. So, this study aimed to investigate whether WZB117 (a specific GLUT1 inhibitor) could enhance the anti-tumor effect of apatinib against melanoma and its potential mechanisms. Methods:We investigated the anti-tumor effects of apatinib alone or in combination with WZB117 on human melanoma cell lines (A375 and SK-MEL-28). The MTT assay determined cell viability and the half-maximal inhibitory concentration (IC50). Multiple drug effect/combination indexes (CI) analysis was conducted to assess interactions between apatinib and WZB117. Signal transducer and activator of transcription 3 (STAT3) pathway measured by western blotting and immunofluorescence staining. RNA expression analyses were performed using the reverse transcriptionquantitative PCR method.Results: Apatinib and WZB117 showed dose and time-dependent growth inhibitory effects in both melanoma cells. The IC50 of apatinib at 48 h in A375 and SK-MEL-28 cells was 62.58 and 59.61 μM, respectively, while the IC50 of WZB117 was 116.85 and 113.91 μM, respectively. The CI values of the two drugs were 0.538 and 0.544, respectively, indicating a synergistic effect of apatinib combined with WZB117. We also found that glucose consumption and lactate production were suppressed by apatinib plus WZB117 in a dosedependent manner, paralleled by reducing glycolytic enzyme pyruvate kinase M2 (PKM2). The potential mechanism of the combination was to suppress the phosphorylation of STAT3. Knockdown of STAT3 by siRNA inhibited the expression of PKM2, while the activation of STAT3 by IL-6 increased the expression of PKM2. The effects of IL-6 were attenuated by apatinib combined with WZB117 treatment.

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supporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis

Zhang

Li²,

Liu³

et al. 2022

Front. Pharmacol.

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“…This is in agreement with the numerous studies reporting an association between imatinib resistance and increased rates of glycolysis [68] , [69] , [70] , [71] , [72] . Furthermore, a recent report showed that the inhibition of glucose transporter GLUT1, the first rate-limiting factor in the glucose metabolic pathway, overcomes imatinib resistance [73] . Notably, an enhanced glycolysis and related disruptions in mitochondrial metabolism are common functional markers of many TKIs-resistant cells [74] .…”

Section: Discussionmentioning

confidence: 99%

Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice

Macioszek¹,

Dudzik²,

Bartoszewski³

et al. 2023

Translational Oncology

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“…In contrast, the expression of GLUT-1 and these glycolytic pathway components increases after the treatment of IM-resistant GIST cell lines using IM ( Figure 1B ). This indicates that IM-resistant GIST cells have a higher glycolysis rate than IM-sensitive GIST cells ( 48 ).…”

Section: Mechanisms Of Secondary Resistance To Imatinibmentioning

confidence: 99%

“…Most of the research viewpoints on energy metabolism in GIST cells have reached a consensus, which provides a theoretical basis for overcoming resistance to IM from the perspective of abnormal energy metabolism. Therapy involving the inhibition of the energy metabolism pathway combined with IM, such as VLX600 combined with IM and WZB117 combined with IM, requires further preclinical validation ( 46 , 48 ).…”

Section: Mechanisms Of Secondary Resistance To Imatinibmentioning

confidence: 99%

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors

Wang

et al. 2022

Front. Oncol.

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.

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Glucose transporter‑1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells

Cited by 19 publications

References 56 publications

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis

Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors

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