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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

Selection of compounds that can be used to modulate HIF1α pathway.
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Figure 3: Selection of compounds that can be used to modulate HIF1α pathway.

Mentions: Recently and because of its central role in tumor progression, HIF1α has become the target of an increasing number of inhibitors developed with the aim to block or reduce tumor growth and possibly progression (Semenza, 2012; Xia et al., 2012; Figure 2). However, it must be noted that most of these compounds are FDA approved molecules used for treatment of cancer or other pathologies or natural products and that most of the studies and discoveries on inhibitors or activators of HIF1α have been made in cell-based systems or xenografts by research laboratories and not by pharmaceutical companies (Semenza, 2012). Inhibitors identified so far exert their action through a variety of different mechanisms ranging from decreased mRNA and protein levels of HIF1α, to prevention of HIF1α dimerization or DNA binding, to inhibition of HIF1α binding to co-activators. Some representative compounds acting at different steps of HIF1α pathway are reported on Figure 3.


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)

Selection of compounds that can be used to modulate HIF1α pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Selection of compounds that can be used to modulate HIF1α pathway.
Mentions: Recently and because of its central role in tumor progression, HIF1α has become the target of an increasing number of inhibitors developed with the aim to block or reduce tumor growth and possibly progression (Semenza, 2012; Xia et al., 2012; Figure 2). However, it must be noted that most of these compounds are FDA approved molecules used for treatment of cancer or other pathologies or natural products and that most of the studies and discoveries on inhibitors or activators of HIF1α have been made in cell-based systems or xenografts by research laboratories and not by pharmaceutical companies (Semenza, 2012). Inhibitors identified so far exert their action through a variety of different mechanisms ranging from decreased mRNA and protein levels of HIF1α, to prevention of HIF1α dimerization or DNA binding, to inhibition of HIF1α binding to co-activators. Some representative compounds acting at different steps of HIF1α pathway are reported on Figure 3.

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