1, 9-Pyrazoloanthrones Downregulate HIF-1α and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy

Lü, Yang; Li, Xinqun; Lu, Haiquan; Fan, Zhen

doi:10.1371/journal.pone.0015823

Cited by 16 publications

(23 citation statements)

References 40 publications

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“…To determine whether 1-methyl-1, 9 PA could mimic the effect of HIF-1α silencing on sensitizing cisplatin-resistant ovarian cancer cells to cisplatin, we first confirmed that 1-methyl-1, 9 PA could downregulate HIF-1α in A2780, A2780/CP, PEO1, and PEO4 cells, as we previously reported it did in many other cancer cell lines [31]. We then determined whether 1-methyl-1, 9 PA could improve the response of the cells to cisplatin treatment in an HIF-1α downregulation-dependent manner.…”

Section: Resultssupporting

confidence: 58%

“…We previously reported that a derivative of 1, 9-pyrazoloanthrone (1, 9 PA), 1-methyl-1, 9 PA, can induce strong downregulation of HIF-1α in multiple types of cancer cells by promoting HIF-1α protein degradation via the ubiquitination pathway [31]. To determine whether 1-methyl-1, 9 PA could mimic the effect of HIF-1α silencing on sensitizing cisplatin-resistant ovarian cancer cells to cisplatin, we first confirmed that 1-methyl-1, 9 PA could downregulate HIF-1α in A2780, A2780/CP, PEO1, and PEO4 cells, as we previously reported it did in many other cancer cell lines [31].…”

Section: Resultsmentioning

confidence: 99%

“…We used a small molecule compound, 1-methyl-1, 9 PA, that we previously reported can promote HIF-1α degradation [31]. 1-methyl-1, 9 PA downregulated HIF-1α level as did cisplatin but apparently via a different mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis was measured by detection of PARP cleavage using Western blotting with an antibody that recognizes both cleaved and uncleaved PARP (Cell Signaling Technology); by quantitative measurement of the levels of cytoplasmic histone-associated DNA fragments (mononucleosomes and oligonucleosomes) using a colorimetric Cell Death Detection ELISA kit (Roche Diagnostics Corp.); or by quantitative measurement of apoptotic cells using a flow cytometer after staining of cells with FITC-conjugated annexin V and propidium iodide (Life Technologies), according to the vendor’s protocols [24,31]. …”

Section: Methodsmentioning

confidence: 99%

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Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

et al. 2016

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Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells towards mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer.

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Section: Resultssupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

et al. 2016

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“…For measurement of cell proliferation, cells were incubated in a 24-well plate with 1 mg/ml 3-(4,5-dimeth-ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) for 2 h at the end of the desired treatments in cell culture [47–49]. Cells were then lysed with a lysis buffer (500 µl/well) containing 20% SDS in dimethyl formamide/H 2 O (1:1, v/v; pH 4.7) at 37°C for at least 6 h. Optical density of the cell lysates was measured at an absorbance wavelength of 570 nm.…”

Section: Methodsmentioning

confidence: 99%

AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis

et al. 2017

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In this study, we expanded our recent work showing that ASCT2, a Na+-dependent neutral amino acid transporter that plays a major role in glutamine uptake in cancer cells, is physically associated with EGFR in human head and neck squamous cell carcinoma cells and in several other types of cancer cells. We found in our current study that ASCT2 can be downregulated by cetuximab, an approved anti-EGFR therapeutic antibody, via cetuximab-induced EGFR endocytosis independently of cetuximab-mediated inhibition of EGFR tyrosine kinase. We further found that ASCT2-EGFR association involves the adaptor-related protein complex 1 gamma 1 subunit (AP1G1), a subunit of clathrin-associated adaptor protein complex 1, which plays a role in membrane protein sorting in endosomes after receptor-mediated endocytosis. We found that AP1G1 is physically associated with both ASCT2 and EGFR and, together with those molecules, forms a heterotrimeric molecular complex. Knockdown of AP1G1 lowered the level of ASCT2-EGFR association, inhibited cetuximab-mediated internalization of ASCT2-EGFR complex, and decreased intracellular glutamine uptake and glutathione biosynthesis. These findings suggest a new therapeutic strategy to overcome cetuximab resistance in cancer cells through combination of cetuximab, which co-targets ASCT2 along with EGFR, with an ROS-inducing agent.

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Mechanisms of Cetuximab Resistance and How to Overcome It

Pauw

Boeckx

Wouters

2021

Critical Issues in Head and Neck Oncology

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Deregulated or increased signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. However, after initially promising results of EGFR-targeted therapies, such as the monoclonal antibody cetuximab, it became clear that both intrinsic and acquired therapeutic resistance are major roadblocks in the field of personalised cancer treatments.In order to unravel and overcome resistance to cetuximab, at least two strategies can be adopted.Firstly, therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signalling and/or mechanisms that can modulate EGFR-dependent signalling. In this chapter, we discuss which mechanisms of cetuximab resistance are already known and which ones deserve further investigation. This enhanced knowledge will guide us to rationally design and test novel combination therapies that overcome resistance to EGFR-targeting agents in cancer treatment.Secondly, an urgent need remains to develop novel targeted treatments for single-agent or combined therapy use. In this view, due to the particular mode of activation of the EGFR receptor, involving ligand-induced homo- and heterodimerization of the four HER receptors, an increased inhibition scope of HER receptors most likely results in a more potent blockade of the HER network, preventing premature emergence of resistance and leading to a more pronounced therapeutic benefit. We discuss two multitargeted compounds, being MEHD7945A (duligotuzumab) and afatinib, in this chapter.Despite the huge efforts to unravel the molecular landscape of HNSCC, the main clinically validated target remains EGFR. However, immune checkpoints, like programmed cell death protein 1 (PD-1), are gaining clinical approvals as well. We underscore the importance of adopting rational drug combinations to enhance the therapeutic effect of the EGFR-inhibitor cetuximab and highlight the ongoing search for predictive biomarkers, with the ultimate goal of delivering individualized cancer therapy to HNSCC patients.

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1, 9-Pyrazoloanthrones Downregulate HIF-1α and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy

Cited by 16 publications

References 40 publications

Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis

Mechanisms of Cetuximab Resistance and How to Overcome It

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