Hypoxia, Therapeutic Resistance, and Sphingosine 1-Phosphate

Cuvillier, Olivier; Ader, Isabelle; Bouquerel, Pierre; Brizuela, Leyre; Gstalder, Cécile; Malavaud, Bernard

doi:10.1016/b978-0-12-394274-6.00005-4

Cited by 42 publications

(34 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumor tissues often contain hypoxic regions, and studies have shown that tumor cells respond differently to chemotherapeutic agents in hypoxic conditions (≤ 1% O 2 ) compared to tumor cells with physiological oxygen supply (5~7% O 2 ) (18, 19). Moreover, tumor hypoxia is significantly associated with lower overall survival and disease-free survival in several cancers (20–22), and hypoxic tumor cells are known to be more resistant to conventional chemotherapies and radiotherapy than non-hypoxic tumor cells within the same tumor (23, 24).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma

Qin

Roszik

Chattopadhyay

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Melanoma is molecularly and structurally heterogeneous, with some tumor cells existing under hypoxic conditions. Our cell growth assays showed that under controlled hypoxic conditions, BRAF(V600E) melanoma cells rapidly became resistant to vemurafenib. By employing both a three-dimensional (3D) spheroid model and a two-dimensional (2D) hypoxic culture system to model hypoxia in vivo, we identified upregulation of HGF/MET signaling as a major mechanism associated with vemurafenib resistance as compared to 2D standard tissue culture in ambient air. We further confirmed that the upregulation of HGF/MET signaling was evident in drug-resistant melanoma patient tissues and mouse xenografts. Pharmacologic inhibition of the c-Met/Akt pathway restored the sensitivity of melanoma spheroids or 2D hypoxic cultures to vemurafenib.

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma

Qin

Roszik

Chattopadhyay

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Much evidence has demonstrated that a hypoxic microenvironment is conducive to the development and maintenance of cancers [17]. Moreover, cancer cells in hypoxic conditions show more resistance to antineoplastic drugs [18], [19]. Some studies that have tried to explain this phenomenon have found that cells in hypoxic conditions generally divide slower than those in normoxic conditions, rendering therapies that target rapidly growing cells less effective [17].…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Inhibition Reverses Multidrug Resistance in Colon Cancer Cells via Downregulation of MDR1/P-Glycoprotein

et al. 2014

View full text Add to dashboard Cite

BackgroundMultidrug resistance (MDR) is one of the major reasons chemotherapy-based treatments fail. Hypoxia is generally associated with tumor chemoresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance (MDR1) gene/transporter P-glycoprotein (P-gp) remains unclear. This study aims to explore the molecular mechanisms of reversing colon cancer MDR by focusing on the target gene HIF-1α.MethodsA chemotherapeutic sensitivity assay was used to observe the efficiency of MDR reversal in LoVo multicellular spheroids (MCS). The apoptotic level induced by different drugs was examined by flow cytometry (FCM). Binding of HIF-1α to the MDR1 gene promoter was evaluated by Chromatin immunoprecipitation (ChIP). The relationship between HIF-1α/P-gp expression and sensitivity to chemotherapy was analyzed.ResultsThe sensitivity of LoVo MCS to all four chemotherapy drugs was decreased to varying degrees under hypoxic conditions. After silencing the HIF-1α gene, the sensitivities of LoVo MCS to all four chemotherapy drugs were restored. The apoptotic levels that all the drugs induced were all decreased to various extents in the hypoxic group. After silencing HIF-1α, the apoptosis level induced by all four chemotherapy drugs increased. The expression of HIF-1α and P-gp was significantly enhanced in LoVo MCS after treatment with hypoxia. Inhibiting HIF-1α significantly decreased the expression of MDR1/P-gp mRNA or protein in both the LoVo monolayers and LoVo MCS. The ChIP assay showed that HIF-1α was bound to the MDR1 gene promoter. Advanced colon carcinoma patients with expression of both HIF-1α and P-gp were more resistant to chemotherapy than that with non expression.ConclusionsHIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-gp. The expression of HIF-1α and MDR1/P-gp can be used as a predictive marker for chemotherapy resistance in colon cancer.

show abstract

“…Chronic hypoxic conditions caused by growing tumor results in release of cytokines/chemokines such as IL-1β, IL-6, IL-8, IL-12, IFN-γ, TNF-α and VEGF causing influx of leukocytes and endothelial cells creating inflammatory conditions. Influx of cells into the hypoxic environment of the tumor microenvironment (TME) can trigger induction of cytokines/growth factors such as IL-6 and VEGF by the endothelial cells that can further support neoangiogenesis and tumor growth [41]. Endothelial cells in the TME are known to express multi-drug resistance genes that contribute to therapy resistance [42].…”

Section: Hypoxia and Its Role In Therapy Resistancementioning

confidence: 99%

“…Altered cell metabolism due to hypoxia is known to be one of the mechanisms contributing to therapy resistance [34,35].…”

Section: Hypoxia and Its Role In Therapy Resistancementioning

confidence: 99%

The Role of Tumor Microenvironment in Melanoma Therapy Resistance

2016

View full text Add to dashboard Cite

Melanoma patients develop resistance to both chemotherapy and targeted-therapy drugs. Promising preclinical and clinical results with immune checkpoint inhibitors using antibodies directed against cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 have re-energized the field of immune-based therapies in melanoma. However, similar to chemotherapy or targeted therapies, immune checkpoint blockade responds in only subsets of melanoma patients. A number of factors, including gene mutations, altered cell-signaling pathways and tumor heterogeneity can contribute to therapy resistance. Recent studies have highlighted the role of inflammatory tumor microenvironment on therapy resistance of cancer cells. Cancer cells either alone or in conjunction with the tumor stroma can contribute to an inflammatory microenvironment. Multimodal approaches of targeting the tumor microenvironment, in addition to malignant cells, may be necessary for better therapy responses.

show abstract

Hypoxia, Therapeutic Resistance, and Sphingosine 1-Phosphate

Cited by 42 publications

References 153 publications

Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma

Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma

HIF-1α Inhibition Reverses Multidrug Resistance in Colon Cancer Cells via Downregulation of MDR1/P-Glycoprotein

The Role of Tumor Microenvironment in Melanoma Therapy Resistance

Contact Info

Product

Resources

About