Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha

Yun, Ba Da; Son, Seung Wan; Choi, Soo Young; Kuh, Hyo-Jeong; Oh, Tae‐Jin; Park, Jong Kook

doi:10.3390/ijms22189819

Cited by 15 publications

(6 citation statements)

References 229 publications

(265 reference statements)

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“…Studies observed that GBM with a high glycolysis rate, which means higher lactate secretion ability, was associated with extensive transcription factor network alternation ( 60 ). Since HIF1α is a critical transcription factor and several studies reported its constant expression under non-hypoxic circumstance ( 61 – 63 ), the high lactate secretion ability of GBM may also result from abnormal regulation of the transcription factor network. Nevertheless, this hypothesis still requires massive experiments to support and validate.…”

Section: Discussionmentioning

confidence: 99%

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

et al. 2023

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IntroductionGlioblastoma is a malignant brain tumor with poor prognosis. Lactate is the main product of tumor cells, and its secretion may relate to immunocytes’ activation. However, its role in glioblastoma is poorly understood. MethodsThis work performed bulk RNA-seq analysis and single cell RNA-seq analysis to explore the role of lactate in glioblastoma progression. Over 1400 glioblastoma samples were grouped into different clusters according to their expression and the results were validated with our own data, the xiangya cohort. Immunocytes infiltration analysis, immunogram and the map of immune checkpoint genes’ expression were applied to analyze the potential connection between the lactate level with tumor immune microenvironment. Furthermore, machine learning algorithms and cell-cell interaction algorithm were introduced to reveal the connection of tumor cells with immunocytes. By co-culturing CD8 T cells with tumor cells, and performing immunohistochemistry on Xiangya cohort samples further validated results from previous analysis.DiscussionIn this work, lactate is proved that contributes to glioblastoma immune suppressive microenvironment. High level of lactate in tumor microenvironment can affect CD8 T cells’ migration and infiltration ratio in glioblastoma. To step further, potential compounds that targets to samples from different groups were also predicted for future exploration.

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Section: Discussionmentioning

confidence: 99%

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

et al. 2023

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“…This result was reproduced in monocytes from HVs when the HIF-1α pathway was induced by the prolyl hydroxylase inhibitor DMOG. Some other studies have proposed regulation of this pathway by garlic-derived compounds and similar antioxidant phytochemicals [ 41 , 42 ]. Along these lines, allicin and diallyl trisulfide suppressed the HIF-1α pathway in cancer and other pathogenic contexts [ 3 , 4 , 7 , 13 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Thiosulfinate-Enriched Allium sativum Extract Exhibits Differential Effects between Healthy and Sepsis Patients: The Implication of HIF-1α

Avendaño-Ortíz

Redondo‐Calvo

Lozano-Rodríguez³

et al. 2023

IJMS

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Garlic (Allium sativum) has historically been associated with antioxidant, immunomodulatory, and microbiocidal properties, mainly due to its richness in thiosulfates and sulfur-containing phytoconstituents. Sepsis patients could benefit from these properties because it involves both inflammatory and refractory processes. We evaluated the effects of thiosulfinate-enriched Allium sativum extract (TASE) on the immune response to bacterial lipopolysaccharide (LPS) by monocytes from healthy volunteers (HVs) and patients with sepsis. We also explored the TASE effects in HIF-1α, described as the key transcription factor leading to endotoxin tolerance in sepsis monocytes through IRAK-M expression. Our results showed TASE reduced the LPS-triggered reactive oxygen species (ROS) production in monocytes from both patients with sepsis and HVs. Moreover, this extract significantly reduced tumor necrosis factor (TNF)-α, interleukin-1β, and interleukin-6 production in LPS-stimulated monocytes from HVs. However, TASE enhanced the inflammatory response in monocytes from patients with sepsis along with increased expression of human leukocyte antigen-DR. Curiously, these dual effects of TASE on immune response were also found when the HV cohort was divided into low- and high-LPS responders. Although TASE enhanced TNFα production in the LPS-low responders, it decreased the inflammatory response in the LPS-high responders. Furthermore, TASE decreased the HIF-1α pathway-associated genes IRAK-M, VEGFA and PD-L1 in sepsis cells, suggesting HIF-1α inhibition by TASE leads to higher cytokine production in these cells as a consequence of IRAK-M downregulation. The suppression of this pathway by TASE was confirmed in vitro with the prolyl hydroxylase inhibitor dimethyloxalylglycine. Our data revealed TASE’s dual effect on monocyte response according to status/phenotype and suggested the HIF-1α suppression as the possible underlying mechanism.

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“…IA 1 is among the most frequently studied proangiogenic phytochemicals, but increased rates of angiogenesis are tightly associated with cancer (Li et al, 2022). IA was reported to have anticarcinogenic activity and to obstruct the progression of cancer (Yun et al, 2021). The SwissADME online server (http://www.swissadme.ch/) was applied to evaluate the drug likeliness of IA 1 and IA.…”

Section: Common Pharmacological Targets Of Ia and Iamentioning

confidence: 99%

Metabolic and Pharmacokinetic Investigation of Ilexsaponin A₁ in Normal and Antibiotic-treated Rats

Cao,

Wang,

Shen

et al. 2023

Pharmacognosy Magazine

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Background Ilexsaponin A1 (IA1) is a bioactive triterpene saponin derived from natural medicinal plants. IA1 exhibits anti-inflammatory and proangiogenic activities and improves intestinal barrier function. It has been reported that IA1 could be metabolized into a dominant metabolite, ilexgenin A (IA) by β-glucosidase enzymes in intestinal microflora. Materials and Methods Herein, an accurate, sensitive, and selective method based on ultra-performance liquid chromatography coupled with mass spectrometry was established to simultaneously profile the metabolism and pharmacokinetic behaviors of IA1 in normal and antibiotic-treated rat plasma after intragastric administration of IA1. The precursor-to-product ion pairs of IA and IA1 were m/ z 501.32↓439.32 and m/ z 663.38↓501.32, respectively. For method validation, the specificity, matrix effect, accuracy, precision, and stability of the pharmacokinetic study were measured, and a calibration curve was created. The collaborative pharmacological target pathways of IA1 and its metabolite IA were investigated using network pharmacology tools. Results The validated analytical method was successfully utilized to investigate the pharmacokinetics of IA1 in normal and antibiotic-treated rats. The bioavailability of IA1 and conversion from IA1 to IA were significantly inhibited by antibiotic-treated rats after oral administration of IA1. Fragment ions at m/z 483.3155, 455.3159, 439.3233, 421.3136, 395.3362, 152.9952, 113.0256, and 71.0531 were characteristic of the IA1 moiety. IA1 was metabolized in rat plasma by biotransformation routes involving deglycosylation, decarboxylation, isomerization, hydrogenation, dehydrogenation, and oxidation. Considering database analysis, IA and IA1 play synergistic role in common pharmacological pathways, such as hypertrophic cardiomyopathy and dilated cardiomyopathy. Conclusion The experiments illustrated that β-glucosidase activity inhibited by antibiotics suppressed the hydrolysis reaction of IA1 in the intestinal tract. IA1 and IA play a synergistic role in exerting effects.

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Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha

Cited by 15 publications

References 229 publications

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Thiosulfinate-Enriched Allium sativum Extract Exhibits Differential Effects between Healthy and Sepsis Patients: The Implication of HIF-1α

Metabolic and Pharmacokinetic Investigation of Ilexsaponin A₁ in Normal and Antibiotic-treated Rats

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Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha

Cited by 15 publications

References 229 publications

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Thiosulfinate-Enriched Allium sativum Extract Exhibits Differential Effects between Healthy and Sepsis Patients: The Implication of HIF-1α

Metabolic and Pharmacokinetic Investigation of Ilexsaponin A1 in Normal and Antibiotic-treated Rats

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Metabolic and Pharmacokinetic Investigation of Ilexsaponin A₁ in Normal and Antibiotic-treated Rats