Low-Glucose Conditions of Tumor Microenvironment Enhance Cytotoxicity of Tetrathiomolybdate to Neuroblastoma Cells

Navrátilová, Jarmila; Hankeová, Tereza; Beneš, Petr; Šmarda, Jan

doi:10.1080/01635581.2013.789118

Cited by 15 publications

(10 citation statements)

References 58 publications

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“…Using neuroblastoma cells (SH-SY5Y and SK-N-BE) Navratilova et al demonstrated that tetrathiomolybdate (TMD), a drug that exhibits anti-angiogenic and tumor-suppressing effects increased glucose uptake, production of lactate, and activation of Akt and AMPK signaling pathways as angiogenic “escape strategies” of NB cells under low glucose conditions 125 . Under low glucose conditions, these effects lead to a significant decrease of intracellular ATP supply and apoptosis.…”

Section: Clinical Implications Of the Tumor Macroenviromentmentioning

confidence: 99%

Tumor Macroenvironment and Metabolism

Al-Zhoughbi

Huang

Paramasivan

et al. 2014

Seminars in Oncology

142

112

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In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%–20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient’s outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described.

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Section: Clinical Implications Of the Tumor Macroenviromentmentioning

confidence: 99%

Tumor Macroenvironment and Metabolism

Al-Zhoughbi

Huang

Paramasivan

et al. 2014

Seminars in Oncology

142

112

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“…The contribution of the TME to this effect has not been well explored and is thus poorly understood. There is some suggestion that dietary restriction leading toward low glucose concentration may inhibit the Warburg effect and increase cytotoxicity in neuroblastoma cell lines [81]. …”

Section: Role Of the Tme In The Hallmarks Of Neuroblastomamentioning

confidence: 99%

More than the genes, the tumor microenvironment in neuroblastoma

et al. 2016

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Neuroblastoma is the second most common solid tumor in children. Since the seminal discovery of the role of amplification of the MYCN oncogene in the pathogenesis of neuroblastoma in the 1980s, much focus has been on the contribution of genetic alterations in the progression of this cancer. However it is now clear that not only genetic events play a role but that the tumor microenvironment (TME) substantially contributes to the biology of neuroblastoma. In this article, we present a comprehensive review of the literature on the contribution of the TME to the ten hallmarks of cancer in neuroblastoma and discuss the mechanisms of communication between neuroblastoma cells and the TME that underlie the influence of the TME on neuroblastoma progression. We end our review by discussing how the knowledge acquired over the last two decades in this field is now leading to new clinical trials targeting the TME.

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“…Usually, Hsp72 is upregulated in response to stress stimuli, and is thought to enhance heat shock tolerance and restore systemic balance [6]. Following extrinsic and intrinsic stressors, including cytotoxic drugs, UV irradiation, low pH [7], limited glucose [8], and hypoxia [9], tumour cells express uncommonly high levels of both Hsp72 and Hsc70 constitutively [10]. Increased expression of Hsp72 and Hsc70 has been implicated in tumour pro-survival through modulation of critical cell-signalling pathways that control cell fate.…”

Section: Introductionmentioning

confidence: 99%

Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis

Amusengeri

Bishop

2019

Molecules

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The human heat shock proteins (Hsps), predominantly Hsp72 and Hsp90, have been strongly implicated in various critical stages of oncogenesis and progression of human cancers. While drug development has extensively focused on Hsp90 as a potential anticancer target, much less effort has been put against Hsp72. This work investigated the therapeutic potential of Hsp72 and its constitutive isoform, Hsc70, via in silico-based screening against the South African Natural Compounds Database (SANCDB). A comparative modeling approach was used to obtain nearly full-length 3D structures of the closed conformation of Hsp72 and Hsc70 proteins. Molecular docking of SANCDB compounds identified one potential allosteric modulator, Discorhabdin N, binding to the allosteric β substrate binding domain (SBDβ) back pocket, with good binding affinities in both cases. This allosteric region was identified in one of our previous studies. Subsequent all-atom molecular dynamics simulations and free energy calculations exhibited promising protein–ligand association characteristics, indicative of strong binding qualities. Further, we utilised dynamic residue network analysis (DRN) to highlight protein regions actively involved in cross-domain communication. Most residues identified agreed with known allosteric signal regulators from literature, and were further investigated for the purpose of deducing meaningful insights into the allosteric modulation properties of Discorhabdin N.

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Low-Glucose Conditions of Tumor Microenvironment Enhance Cytotoxicity of Tetrathiomolybdate to Neuroblastoma Cells

Cited by 15 publications

References 58 publications

Tumor Macroenvironment and Metabolism

Tumor Macroenvironment and Metabolism

More than the genes, the tumor microenvironment in neuroblastoma

Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis

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