Obatoclax as a perpetrator in drug–drug interactions and its efficacy in multidrug resistance cell lines

Theile, Dirk; Allendorf, David H.; Köhler, Bruno; Jassowicz, Adam; Weiß, Johanna

doi:10.1111/jphp.12455

Cited by 5 publications

(2 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A significant MRP2 induction was observed when used at a similar range of concentrations found in patients under treatment with the drug. Simultaneous activation of PXR suggests mediation by this nuclear receptor (Theile et al, 2015a). Similarly, the experimental bcl-2 inhibitor obatoclax induced MRP2 in the same cell line.…”

Section: Anticancer Agentsmentioning

confidence: 79%

Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

Tocchetti

Rigalli

Arana

et al. 2016

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Section: Anticancer Agentsmentioning

confidence: 79%

Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

Tocchetti

Rigalli

Arana

et al. 2016

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

“…BH3 mimetics bind to the hydrophobic groove of antiapoptotic proteins mimicking the action of BH3-only proteins in binding to pro-survival proteins, leading to the release of BH3-only proteins from complexes and activation of BAX and BAK. So far, nearly a dozen BH3 mimetics are under investigation as Bcl-2 inhibitors in different phases of human clinical trials such as AT-101 (R-(−)-gossypol) [ 83 , 84 ], ABT-199 (venetoclax) [ 85 ], ABT-737 [ 86 ], ABT-263 (navitoclax, orally available derivative of ABT-737) [ 87 , 88 ], GX15-070 (obatoclax) [ 89 , 90 ] and TW37 [ 91 ]. The field of inhibitors of Bcl-2 family members is in continuous development [ 92 , 93 ], underscoring the importance of these molecules as potent anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Pistritto

Trisciuoglio²,

Ceci

et al. 2016

Aging

1,255

792

View full text Add to dashboard Cite

Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.

show abstract

Modulation of ABC Transporters by Nuclear Receptors: Physiological, Pathological and Pharmacological Aspects

Rigalli

Tocchetti

Weiß

2019

CMC

View full text Add to dashboard Cite

ABC transporters are membrane proteins mediating the efflux of endo- and xenobiotics. Transporter expression is not static but instead is subject to a dynamic modulation aiming at responding to changes in the internal environment and thus at maintaining homeostatic conditions. Nuclear receptors are ligand modulated transcription factors that get activated upon changes in the intracellular concentrations of the respective agonists and bind to response elements within the promoter of ABC transporters, thus modulating their expression and, consequently, their activity. This review compiles information about transporter regulation by nuclear receptors classified according to the perpetrator compounds and the biological effects resulting from the regulation. Modulation by hormone receptors is involved in maintaining endocrine homeostasis and may also lead to an altered efflux of other substrates in cases of altered hormonal levels. Xenobiotic receptors play a key role in limiting the accumulation of potentially harmful compounds. In addition, their frequent activation by therapeutic agents makes them common molecular elements mediating drug-drug interactions and cancer multidrug resistance. Finally, lipid and retinoid receptors are usually activated by endogenous molecules, thus sensing metabolic changes and inducing ABC transporters to counteract potential alterations. Furthermore, the axis nuclear receptor-ABC transporter constitutes a promising therapeutic target for the treatment of several disease states like cancer, atherosclerosis and dyslipidemia. In the current work, we summarize the information available on the pharmacological potential of nuclear receptor modulators and discuss their applicability in the clinical practice.

show abstract

Obatoclax as a perpetrator in drug–drug interactions and its efficacy in multidrug resistance cell lines

Abstract: Obatoclax retains its efficacy in cells overexpressing P-gp, MRP2 or BCRP and might act as a perpetrator drug in interactions with drugs, for example being substrates of CYP1A2 or BCRP.

Cited by 5 publications

References 60 publications

Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Modulation of ABC Transporters by Nuclear Receptors: Physiological, Pathological and Pharmacological Aspects

Contact Info

Product

Resources

About