Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part I

Wilczyński, Jacek R.; Duechler, Markus; Czyż, Małgorzata

doi:10.1007/s00005-011-0131-4

Cited by 27 publications

(24 citation statements)

References 120 publications

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“…6 HIF-1 α can induce the expression of multiple target genes such as VEGF 29 (an important angiogenesis factor), CXCR4 30 (an important factor regulating cell migration), adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) 31 (a pro-cell death member of the Bcl-2 family) and CAIX 31 (a marker for hypoxia). Thus, HIF-1 α can activate downstream pathways involved in proliferation, metabolism, differentiation and angiogenesis, 32, 33 which likely account for the ability of HIF-1 α to keep leukemic blasts at undifferentiated stages and therefore maintain a larger number of LSCs in the bone marrow. 34 It has been shown that silencing HIF-1 α in Jurkat cells significantly decreased their migration and infiltration capacity.…”

Section: Discussionmentioning

confidence: 99%

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

et al. 2013

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Leukemia stem cells (LSCs) are considered to be the main reason for relapse and are also regarded as a major hurdle for the success of acute myeloid leukemia chemotherapy. Thus, new drugs targeting LSCs are urgently needed. Triptolide (TPL) is cytotoxic to LSCs. Low dose of TPL enhances the cytotoxicity of idarubicin (IDA) in LSCs. In this study, the ability of TPL to induce apoptosis in leukemic stem cell (LSC)-like cells derived from acute myeloid leukemia cell line KG1a was investigated. LSC-like cells sorted from KG1a were subjected to cell cycle analysis and different treatments, and then followed by in vitro methyl thiazole tetrazolium bromide cytotoxicity assay. The effects of different drug combinations on cell viability, intracellular reactive-oxygen species (ROS) activity, colony-forming ability and apoptotic status were also examined. Combination index-isobologram analysis indicates a synergistic effect between TPL and IDA, which inhibits the colony-forming ability of LSC-like cells and induces their apoptosis. We further investigated the expression of Nrf2, HIF-1α and their downstream target genes. LSC-like cells treated with both TPL and IDA have increased levels of ROS, decreased expression of Nrf2 and HIF-1α pathways. Our findings indicate that the synergistic cytotoxicity of TPL and IDA in LSCs-like cells may attribute to both induction of ROS and inhibition of the Nrf2 and HIF-1α pathways.

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Section: Discussionmentioning

confidence: 99%

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

et al. 2013

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“…Again, many natural products mostly with anti-inflammatory properties are NFkB inhibitors (Gupta et al, 2010). More than 700 inhibitors of NFkB have been identified so far and their importance is due to the central role that this transcription factor has for many pathologies, beside inflammation and cancer (Wilczynski et al, 2011). Some representative compounds acting at different steps of NFkB pathway are reported on Figure 5.…”

Section: Modulators Of Nfkb and Nfkb-dependent Genesmentioning

confidence: 99%

“…In particular, parthenolide seems to have an anti-tumoral activity also on cancer stem cells (Gunn et al, 2011). Anti-inflammatory drugs are IKK inhibitors although with an unknown mechanisms (Wilczynski et al, 2011). Among these there are: aspirin, ibuprofen, sulindac, sulfasalazine, and other NSAIDs (Kast, 2006).…”

Section: Modulators Of Nfkb and Nfkb-dependent Genesmentioning

confidence: 99%

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

Tafani¹,

Pucci²,

Russo³

et al. 2013

Front. Pharmacol.

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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.

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“…1,2 Limited evidence of efficacy in clinical trials exists, although some TF antagonists (STAT3, -κB) are progressing through phase 1-2 trials. 3,4 …”

Section: Introductionmentioning

confidence: 99%

A Novel Mithramycin Analogue with High Antitumor Activity and Less Toxicity Generated by Combinatorial Biosynthesis

et al. 2012

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Mithramycin is an antitumor compound produced by Streptomyces argillaceus that has been used for the treatment of several types of tumors and hypercalcaemia processes. However, its use in humans has been limited because its side effects. Using combinatorial biosynthesis approaches, we have generated seven new mithramycin derivatives, which either differ from the parental compound in the sugar profile or in both the sugar profile and the 3-side chain. From these studies three novel derivatives were identified, demycarosyl-3D-β-d-digitoxosyl-mithramycin SK, demycarosyl-mithramycin SDK and demycarosyl-3D-β-d-digitoxosyl-mithramycin SDK, which show high antitumor activity. The first one, which combines two structural features previously found to improve pharmacological behavior, was generated following two different strategies, and it showed less toxicity than mithramycin. Preliminary in vivo evaluation of its antitumor activity through hollow fiber assays, and in subcutaneous colon and melanoma cancers xenografts models, suggests that demycarosyl-3D-β-d-digitoxosyl-mithramycin SK could be a promising antitumor agent, worthy of further investigation.

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Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part I

Cited by 27 publications

References 120 publications

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

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

A Novel Mithramycin Analogue with High Antitumor Activity and Less Toxicity Generated by Combinatorial Biosynthesis

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