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Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review

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Abstract

Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment.

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Abbreviations

2-ME2:

2-Methoxyestradiol

AMPK:

AMP-activated protein kinase

ARNT:

Aryl hydrocarbon nuclear translocator

Bcl-2:

B-cell lymphoma 2

Bcl-xL:

B-cell lymphoma-extra-large

BDNF:

Brain-derived neurotrophic factor

CaMKIIγ:

Ca2+/calmodulin-dependent protein kinase II-γ

CLDN:

Claudin

COX-2:

Cyclooxygenase-2

CXCL:

C-X-C chemokine receptor ligand

Cyt c:

Cytochrome c

DHTMF:

5,3′-Dihydroxy-6,7,4′-trimethoxyflavanone

DNMTs:

DNA methyltransferases

EGCG:

Epigallocatechin-3 gallate

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

EPO:

Erythropoietin

ER-α:

Estrogen receptor-α

ERK:

Extracellular signal-regulated protein kinase

FGFR3:

Fibroblast growth factor receptor 3

FIH:

Factor inhibiting HIF

FUT4:

Fucosyltransferase 4

G6PD:

Glucose-6-phosphate dehydrogenase

Gli1:

Glioma-associated oncogene homolog 1

GLUT:

Glucose transporter

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

GSK-3β:

Glycogen synthase kinase-3β

HDACs:

Histone deacetylases

HGF:

Hepatocyte growth factor

HIF-1α:

Hypoxia-inducible factor-1α

HK2:

Hexokinase 2

HL:

Hippel-Lindau

IGF-2:

Insulin-growth factor-2

IκB:

Inhibitor of nuclear factor-κB

IKKβ:

IκB kinase β

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

JAK:

Janus kinase

JNK:

C-Jun NH2-terminal kinase

LDH:

Lactate dehydrogenase

LDHA:

Lactate dehydrogenase A

LFCS:

Low-molecular-weight fucosylated chondroitin sulfate

LMWF:

Low-molecular-weight fucoidan

MAPKs:

Mitogen-activated protein kinases

Mcl-1:

Myeloid cell leukemia-1

MDA:

Malondialdehyde

MMPs:

Matrix metalloproteinases

MTA1:

Metastasis-associated protein 1

mTOR:

Mammalian target of rapamycin

NCs:

Natural compounds

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B-cell

NOS2:

Nitric oxide synthase 2

Nrf2:

Nuclear factor erythroid 2-related factor 2

NSCLC:

Non-small cell lung cancer

OCLN:

Occluding

P4Hs:

Prolyl-4-hydroxylases

PARP:

Poly (ADP ribose) polymerase

PCNA:

Proliferating cell nuclear antigen

PDGF:

Platelet-derived growth factor

PDK:

Pyruvate dehydrogenase kinase

PHD2:

Prolyl hydroxylase 2

PI3K:

Phosphatidylinositol 3-kinases

PK:

Pyruvate kinase

PKB:

Protein kinase B

PKC:

Protein kinase C

PLCγ1:

Phospholipase C gamma1

PPAR-γ:

Peroxisome proliferator–activated receptor-γ

PRL-3:

Phosphatase of regenerating liver-3

PSTAT3:

Phospho-STAT3

PTEN:

Phosphatase and tensin homolog

PUMA:

P53 upregulated modulator of apoptosis

Raf:

Rapidly accelerated fibrosarcoma

ROS:

Reactive oxygen species

RTKs:

Receptor tyrosine kinases

SHH:

Sonic hedgehog

STAT:

Signal transducer and activator of transcription

TERT:

Telomerase reverse transcriptase

TGF-α:

Transforming growth factor-α

TGF-β:

Transforming growth factor-β

TIMP-1:

Matrix metalloproteinases

TIMP:

Tissue inhibitor of metalloproteinase

TLR3:

Toll-like receptors

TNF-α:

Tumor necrosis factor-α

TRAIL:

TNF-related apoptosis-inducing ligand

uPA:

Urokinase plasminogen activator

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2

ZO-1:

Zona occludens1

α-SMA:

α-Smooth muscle actin

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Author notes

  1. Sajad Fakhri and Seyed Zachariah Moradi contributed equally to this work.

Authors and Affiliations

  1. Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran

    Sajad Fakhri & Seyed Zachariah Moradi

  2. Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran

    Seyed Zachariah Moradi

  3. Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

    Farahnaz Faraji

  4. Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, 6714415153, Iran

    Leila Kooshki

  5. College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL, 34211, USA

    Kassidy Webber & Anupam Bishayee

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  1. Sajad Fakhri
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Contributions

Conceptualization, S.F., and A.B.; methodology and software, S.F., S.Z.M., and F.F.; writing — original draft, S.F., S.Z.M., F.F., L.K. and A.B.; writing — review and editing, S.F., S.Z.M., K.W., and A.B.; visualization, S.F.; supervision, S.F. and A.B.; project administration, A.B.

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Correspondence to Anupam Bishayee.

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Fakhri, S., Moradi, S.Z., Faraji, F. et al. Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review. Cancer Metastasis Rev 43, 501–574 (2024). https://doi.org/10.1007/s10555-023-10136-9

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