Unbiased Metabolic Profiling Predicts Sensitivity of High MYC-Expressing Atypical Teratoid/Rhabdoid Tumors to Glutamine Inhibition with 6-Diazo-5-Oxo-L-Norleucine

Wang, Sabrina; Poore, Brad; Alt, Jesse; Price, Antoinette; Allen, Sariah J.; Hanaford, Allison R.; Kaur, Harpreet; Orr, Brent A.; Slusher, Barbara S.; Eberhart, Charles G.; Raabe, Eric H.; Rubens, Jeffrey

doi:10.1158/1078-0432.ccr-19-0189

Cited by 25 publications

(15 citation statements)

References 47 publications

(85 reference statements)

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“…S2). The results suggested that the regulatory mechanism of CBP in breast cancer mainly involves the induction of apoptosis, which is in line with some published studies 37,38 . Based on the compounds in RJSJ, we obtained 682 targets, 33 of which were also targets of CBP, including ve apoptosis-related genes (Fig.…”

Section: Analysis Of the Potential Synergistic Mechanism Of Rjsj And supporting

confidence: 90%

Ruanjian Sanjie Decoction Induces Apoptosis in Triple-negative Breast Cancer Cells by Downregulating cIAP1/2 and XIAP

Zhao¹,

Wang²,

Jia³

et al. 2020

Preprint

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Background: Traditional Chinese medicine (TCM) comprises a unique theoretical system developed over thousands of years. The previous study reported that Ruanjian Sanjie (RJSJ) exerts anti-tumor effects by inducing cell apoptosis. However, the mechanism is not clear. Methods: In this study, we investigated the possible mechanism by the strategy of combining network pharmacology analysis with experiment (in vitro and in vivo). First, four kinds of breast cancer cell lines were used to conduct proliferation, apoptosis and cell cycle analysis. Secondly, to study pathophysiological processes of breast cancer at the molecular network level, we for the first time constructed an “integrated apoptosis module network of breast cancer” by assembling the regulatory relationships of canonical apoptosis signaling pathways. Through the strategy of combining network analysis and experiments, we analyzed the main mechanism of RJSJ in breast cancer and screened out the core genes. We further studied the inhibitory effect of RJSJ combined with carboplatin (CBP) in vivo. Finally, the synergistic effect of RJSJ and CBP were analyzed and the potential active components in RJSJ were predicted.Results: This study demonstrated that RJSJ could significantly inhibit breast cancer cell proliferation and induce apoptosis in a concentration-dependent manner. The primary mechanism of RJSJ in the treatment of breast cancer was pro-apoptotic. The core apoptosis genes regulated by RJSJ were cIAP1/2 and XIAP. We also found that RJSJ in combination with CBP tended to synergistically induce apoptosis, which might mainly be achieved through the regulation of multiple targets and pathways. Alexandrin (BX05, XKC02, SCG01), baicalin (BX22), guanosine (BX32), arjunglucoside I (XKC10) etc. were predicted as potential active components.Conclusions: These findings provide the rationale for exploring the therapeutic effects of RJSJ against breast cancer and providing a bridge for the combined use of Chinese and Western medicine.

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Section: Analysis Of the Potential Synergistic Mechanism Of Rjsj And supporting

confidence: 90%

Ruanjian Sanjie Decoction Induces Apoptosis in Triple-negative Breast Cancer Cells by Downregulating cIAP1/2 and XIAP

Zhao¹,

Wang²,

Jia³

et al. 2020

Preprint

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“…6-diazo-5-oxo-L-norleucine (DON) and its naturally occurring prodrug azotomycin are diazo analogues of glutamine that irreversibly inhibit multiple glutamine-utilizing enzymes. GA have been observed to cause decreased proliferation or induction of apoptosis, depending on genetic context, cell/tissue type, and environment (16)(17)(18). GA have been tested clinically (19), including for sarcomas (20).…”

Section: Introductionmentioning

confidence: 99%

The Novel Glutamine Antagonist Prodrug JHU395 Has Antitumor Activity in Malignant Peripheral Nerve Sheath Tumor

Lemberg

Zhao

et al. 2020

Molecular Cancer Therapeutics

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The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared with Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. In vivo, orally administered JHU395 delivered active GA to tumors with over 2-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotopelabeled flux analyses in tumors identified multiple glutaminedependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.

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“…CHLA-02 might also have more embryonic phenotypes than CHLA-05 due to high NPM1 gene expression and AFP positivity. This could be due to a high expression of MYC and high glutamine consumption in CHLA-02 [ 67 ]. In breast cancer patients, MYC expression increased the risk of breast cancer brain metastasis [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Human Malignant Rhabdoid Tumor Antigens as Biomarkers and Potential Therapeutic Targets

Hua

Zeng

Chen

et al. 2022

Cancers

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Introduction: Atypical teratoid rhabdoid tumor (ATRT) is a lethal type of malignant rhabdoid tumor in the brain, seen mostly in children under two years old. ATRT is mainly linked to the biallelic inactivation of the SMARCB1 gene. To understand the deadly characteristics of ATRT and develop novel diagnostic and immunotherapy strategies for the treatment of ATRT, this study investigated tumor antigens, such as alpha-fetoprotein (AFP), mucin-16 (MUC16/CA125), and osteopontin (OPN), and extracellular matrix modulators, such as matrix metalloproteinases (MMPs), in different human malignant rhabdoid tumor cell lines. In addition, the roles of MMPs were also examined. Materials and methods: Five human cell lines were chosen for this study, including two ATRT cell lines, CHLA-02-ATRT and CHLA-05-ATRT; a kidney malignant rhabdoid tumor cell line, G401; and two control cell lines, human embryonic kidney HEK293 and HEK293T. Both ATRT cell lines were treated with a broad-spectrum MMP inhibitor, GM6001, to investigate the effect of MMPs on cell proliferation, viability, and expression of tumor antigens and biomarkers. Gene expression was examined using a reverse transcription polymerase chain reaction (RT-PCR), and protein expression was characterized by immunocytochemistry and flow cytometry. Results: All the rhabdoid tumor cell lines tested had high gene expression levels of MUC16, OPN, AFP, and MSLN. Low expression levels of neuron-specific enolase (ENO2) by the two ATRT cell lines demonstrated their lack of neuronal genotype. Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) and tissue inhibitor of metalloproteinases-2 (TIMP-2) were highly expressed in these malignant rhabdoid tumor cells, indicating their invasive phenotypes. GM6001 significantly decreased ATRT cell proliferation and the gene expression of MSLN, OPN, and several mesenchymal markers, suggesting that inhibition of MMPs may reduce the aggressiveness of rhabdoid cancer cells. Conclusion: The results obtained from this study may advance our knowledge of the molecular landscapes of human malignant rhabdoid tumors and their biomarkers for effective diagnosis and treatment. This work analyzed the expression of human malignant rhabdoid tumor antigens that may serve as biomarkers for the development of novel therapeutic strategies, such as cancer vaccines and targeted and immunotherapies targeting osteopontin and mesothelin, for the treatment of patients with ATRT and other malignant rhabdoid tumors.

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Unbiased Metabolic Profiling Predicts Sensitivity of High MYC-Expressing Atypical Teratoid/Rhabdoid Tumors to Glutamine Inhibition with 6-Diazo-5-Oxo-L-Norleucine

Cited by 25 publications

References 47 publications

Ruanjian Sanjie Decoction Induces Apoptosis in Triple-negative Breast Cancer Cells by Downregulating cIAP1/2 and XIAP

Ruanjian Sanjie Decoction Induces Apoptosis in Triple-negative Breast Cancer Cells by Downregulating cIAP1/2 and XIAP

The Novel Glutamine Antagonist Prodrug JHU395 Has Antitumor Activity in Malignant Peripheral Nerve Sheath Tumor

Human Malignant Rhabdoid Tumor Antigens as Biomarkers and Potential Therapeutic Targets

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