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Modulators of HIF1α and NFkB in Cancer Treatment: Is it a Rational Approach for Controlling Malignant Progression?

Tafani M, Pucci B, Russo A, Schito L, Pellegrini L, Perrone GA, Villanova L, Salvatori L, Ravenna L, Petrangeli E, Russo MA - Front Pharmacol (2013)

Bottom Line: Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression.In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies.Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1α and NFkB activity will be outlined.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, Sapienza University of Rome Rome, Italy ; Laboratory of Molecular and Cellular Pathology - Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana Rome, Italy.

ABSTRACT
HIF1α and NFkB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression, and resistance to chemotherapy. In fact, HIF1α and NFkB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic reprograming, inflammatory reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7, and some TLRs, are activated by HIF1α; and that, in turn, alarmin receptors strongly activate NFkB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies. Some of them are undergoing clinical trials and soon they will be used alone or in combination with standard anti-tumoral agents to achieve a better treatment of tumors with reduction of metastasis formation and, more importantly, with a net increase in survival. This review highlights the central role of HIF1α activated in hypoxic regions of the tumor, of NFkB activation and proinflammatory gene expression in transformed cells to understand their progression toward malignancy. Different molecules and strategies to inhibit these transcription factors will be reviewed. Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1α and NFkB activity will be outlined.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the pathway linking hypoxia and HIF1α activation with inflammation and tumor progression.
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Figure 1: Schematic representation of the pathway linking hypoxia and HIF1α activation with inflammation and tumor progression.

Mentions: Hypoxia produces two basic consequences: (a) Necrosis of cells that are more distant from vessels of host tissue; (b) Activation of HIF1α in surviving tumor cells closer to the vessels and sublethally damaged; the HIF1α-driven gene expression allows them to survive and grow increasing their commitment to malignancy (Figure 1).


Modulators of HIF1α and NFkB in Cancer Treatment: Is it a Rational Approach for Controlling Malignant Progression?

Tafani M, Pucci B, Russo A, Schito L, Pellegrini L, Perrone GA, Villanova L, Salvatori L, Ravenna L, Petrangeli E, Russo MA - Front Pharmacol (2013)

Schematic representation of the pathway linking hypoxia and HIF1α activation with inflammation and tumor progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569619&req=5

Figure 1: Schematic representation of the pathway linking hypoxia and HIF1α activation with inflammation and tumor progression.
Mentions: Hypoxia produces two basic consequences: (a) Necrosis of cells that are more distant from vessels of host tissue; (b) Activation of HIF1α in surviving tumor cells closer to the vessels and sublethally damaged; the HIF1α-driven gene expression allows them to survive and grow increasing their commitment to malignancy (Figure 1).

Bottom Line: Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression.In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies.Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1α and NFkB activity will be outlined.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, Sapienza University of Rome Rome, Italy ; Laboratory of Molecular and Cellular Pathology - Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana Rome, Italy.

ABSTRACT
HIF1α and NFkB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression, and resistance to chemotherapy. In fact, HIF1α and NFkB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic reprograming, inflammatory reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7, and some TLRs, are activated by HIF1α; and that, in turn, alarmin receptors strongly activate NFkB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies. Some of them are undergoing clinical trials and soon they will be used alone or in combination with standard anti-tumoral agents to achieve a better treatment of tumors with reduction of metastasis formation and, more importantly, with a net increase in survival. This review highlights the central role of HIF1α activated in hypoxic regions of the tumor, of NFkB activation and proinflammatory gene expression in transformed cells to understand their progression toward malignancy. Different molecules and strategies to inhibit these transcription factors will be reviewed. Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1α and NFkB activity will be outlined.

No MeSH data available.


Related in: MedlinePlus