The Function of Retinoid X Receptor α in Cancer Cells

Huang, Gui Li; Chen, Qing Xi; Shen, Dong

doi:10.4172/2329-6577.1000161

Cited by 4 publications

(9 citation statements)

References 107 publications

(132 reference statements)

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“…COMPARE and hierarchical cluster analyses showed that genes activating apoptosis (CRADD, CASP2) were resistant to crizotinib, while genes regulating angiogenesis (AMOTL2, VEGFB) were sensitive to crizotinib. Our findings matched with another study showing that deletion of hepatocyte RXRα in mice downregulated genes associated with angiogenesis, leading to inhibition of angiogenesis, and upregulated genes related to pro-inflammation, adipogenesis, and apoptosis [26]. Retinoid X receptor (RXR) regulates basic functions in myeloid cells, as pro-angiogenic activity, chemokine secretion, phagocytosis, and inflammatory responses.…”

Section: Discussionsupporting

confidence: 89%

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Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

et al. 2021

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Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.

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Section: Discussionsupporting

confidence: 89%

“…RXRα is an essential feature of the oncogenic complex in APL [25]. Targretin, another RXRα ligand, may serve to treat cutaneous T cell lymphoma [26]. Targretin overcame multidrug resistance in breast cancer and non-small-cell lung cancer [27,28].…”

Section: Discussionmentioning

confidence: 99%

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

et al. 2021

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“…FXR was activated from ALA too, but with the addition of an intense activation of the peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR). When both were activated, FXR and PPAR/RXR form a heterodimer that, in turn, plays a role in cancer growth inhibition [ 176 ].…”

Section: Anticancer Activitymentioning

confidence: 99%

Natural Products to Fight Cancer: A Focus on Juglans regia

Catanzaro

Greco

Potenza

et al. 2018

Toxins

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Even if cancer represents a burden for human society, an exhaustive cure has not been discovered yet. Low therapeutic index and resistance to pharmacotherapy are two of the major limits of antitumour treatments. Natural products represent an excellent library of bioactive molecules. Thus, tapping into the natural world may prove useful in identifying new therapeutic options with favourable pharmaco-toxicological profiles. Juglans regia, or common walnut, is a very resilient tree that has inhabited our planet for thousands of years. Many studies correlate walnut consumption to beneficial effects towards several chronic diseases, such as cancer, mainly due to the bioactive molecules stored in different parts of the plant. Among others, polyphenols, quinones, proteins, and essential fatty acids contribute to its pharmacologic activity. The present review aims to offer a comprehensive perspective about the antitumour potential of the most promising compounds stored in this plant, such as juglanin, juglone, and the ellagitannin-metabolites urolithins or deriving from walnut dietary intake. All molecules and a chronic intake of the fruit provide tangible anticancer effects. However, the scarcity of studies on humans does not allow results to be conclusive.

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“…Rf(Hexan/EtOAc = 87,5:12,5) = 0,57. C NMR (101 MHz,CDCl3) δ = 167,79;142,43;140,32;132,59;130,87;127,17;126,54;60,61;21,87;21,49;14,49. MS (ESI+): m/z 179,26 ([M+H + ]).…”

Section: 4-dimethylbenzoesäureethylester (171)unclassified

“…C NMR (101 MHz,CDCl3) δ = 166,15;142,62;130,16;129,10;126,70;61,22;32,37;14,44. 171,39; 136,71; 134,59; 129,83; 129,37; 61,08; 41,20; 33,33; 14,29.…”

mentioning

confidence: 99%

Entwicklung Subtypen-präferentieller RXR-Liganden

Adouvi

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Bislang sind die strukturellen Voraussetzungen für die Selektivität von Agonisten an den Retinoid Rezeptor Subtypen RXRα, RXRβ und RXRγ kaum erforscht, obwohl RXR-Modulatoren, die eine Subtypen-Präferenz aufweisen, aufgrund der unterschiedlichen Expressionsmuster der Subtypen Gewebe-spezifische Effekte vermitteln und somit Nebenwirkungen verringern könnten. Der Grund dieser Forschungslücke liegt teilweise darin, dass die Entwicklung Subtypen-selektiver RXR-Agonisten aufgrund der enormen strukturellen Ähnlichkeit der Ligandbindestellen in den RXR-Subtypen - alle Aminosäuren, die die Bindungsstellen bilden sind identisch - als unerreichbar angesehen wurde. Die Entdeckung des Naturstoffs Valerensäure als RXR-Agonist mit ausgeprägter Präferenz für den RXRβ-Subtyp hat jedoch gezeigt, dass Subtypen-selektive RXR-Modulation möglich ist249 und SAR-Studien an unterschiedlichen RXR-Ligand-Chemotypen haben in der Folge bestätigt, dass die Entwicklung von RXR-Liganden mit Subtypen-Präferenz erreicht werden kann. Auf der Basis von Valerensäure und der in früheren Arbeiten entwickelten RXR-Agonisten wurden in dieser Arbeit Strukturmodifikationen identifiziert, die zu einer RXR-Subtypen-Präferenz beitragen. Durch die Verschmelzung dieser Strukturelemente ist es gelungen, einen neuen RXR-Agonist-Chemotyp (A) zu entwerfen, der durch strategische Methylierung und weitere Strukturmodifikationen zur Präferenz für jeden Subtyp optimiert werden konnte. In einem Adipozyten-Differenzierungsexperiment konnte gezeigt werden, dass RXRα der wichtigste Heterodimer-Partner von PPARγ während der Adipogenese ist. Ferner unterstrich diese biologische Untersuchung das Potenzial von 99, 103 und 105 als Subtyp-präferentielle RXR-Agonisten in vitro Experimenten zu dienen. Auf der Grundlage dieser Ergebnisse wurde eine mögliche Rolle von Acrylsäurepartialstrukturen natürlicher RXR-Liganden basierend auf dem zuvor entwickelten Chemotyp untersucht. Hierzu wurden das α-Methylacrylsäuremotiv des Naturstoffs Valerensäure (18) und das β-Methylacrylsäuremotiv des endogenen RXR-Agonisten 9-cis-Retinsäure in den Chemotyp A integriert (Chemotyp B), um die Rolle dieser Acrylsäuregruppen bei der Vermittlung der RXR-Subtypen-Selektivität zu untersuchen. Die Strukturmodifikationen an B zeigten, dass nur die α-Methyl-substituierte Acrylsäurekette toleriert bzw. von RXRβ präferiert wurde, was die RXR-Präferenz der Valerensäure (18) unterstützte. In dieser Arbeit konnte gezeigt werden, dass RXR-Liganden mit Subtypen-Präferenz realisierbar sind und durch gezielte Strukturmodifikationen in ihrer Präferenz gesteuert werden können. Die Erkenntnisse zu den Struktur-Wirkungs-Beziehungen der neuen RXR-Agonist-Chemotypen A und B erweitern den Wissenstand über die strukturellen Voraussetzungen von RXR-Liganden für die Subtypen-Präferenz deutlich.

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The Function of Retinoid X Receptor α in Cancer Cells

Cited by 4 publications

References 107 publications

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

Natural Products to Fight Cancer: A Focus on Juglans regia

Entwicklung Subtypen-präferentieller RXR-Liganden

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