Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs

Hasan, Mahmud; Marzouk, Mohamed Akmal; Adhikari, Saugat; Wright, Thomas D.; Miller, Benton P.; Matossian, Margarite D.; Elliott, Steven; Wright, Maryl; Alzoubi, Madlin; Collins‐Burow, Bridgette M.; Burow, Matthew E.; Holzgrabe, Ulrike; Zlotos, Darius P.; Stratford, Robert E.; Witt‐Enderby, Paula A.

doi:10.1124/mol.119.116202

Cited by 35 publications

(49 citation statements)

References 46 publications

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“…Selection of compounds aiming at the melatoninergic system as tools. 46 : D600, the only MT 1 ‐only ligand 127 ; 47 : attempt to have a fluorescent ligand 144 ; 48 : ICOA‐9: the first—and only—cell‐impermeant melatonin receptor agonist 143 ; 49 : Magnalol derivatives as melatonin receptor ligand 150 ; 50 : Curcumin‐melatonin hybrid with new properties 145 ; 51 : Tamoxifen‐melatonin hybrid 147 …”

Section: Unique Pharmacophores and Some Pharmacological Toolsmentioning

confidence: 99%

“…Due to the claimed antioxidant property of melatonin, several groups have been attracted by the idea of synthesizing mixed compounds, for example, melatonin linked to the “multi‐active” molecule curcumin 145,146 or melatonin linked to the selective estrogen receptor modulator, tamoxifen 147 . Other examples of dually acting ligands are hybrids composed of MT 1 /MT 2 agonists and fatty acid amide hydrolase inhibitor 148 and of melatonin linked to p‐benzoquinone methide 149 .…”

Section: Unique Pharmacophores and Some Pharmacological Toolsmentioning

confidence: 99%

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Melatonin receptor ligands: A pharmaco‐chemical perspective

Boutin

Witt‐Enderby

Sotriffer

et al. 2020

Journal of Pineal Research

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Melatonin MT1 and MT2 receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT2‐selective agents—agonists, antagonists, or partial agonists—were reported, the field was lacking MT1‐selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri‐ or tetra‐cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype‐selective melatonin receptor antagonists “active” in vivo, which are critical to our understanding of melatonin and melatonin receptors’ role in basic physiology and disease.

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Section: Unique Pharmacophores and Some Pharmacological Toolsmentioning

confidence: 99%

Section: Unique Pharmacophores and Some Pharmacological Toolsmentioning

confidence: 99%

Melatonin receptor ligands: A pharmaco‐chemical perspective

Boutin

Witt‐Enderby

Sotriffer

et al. 2020

Journal of Pineal Research

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“…It is known that TMX use may eventually lead to resistance. However, this seems to be overcome by the novel MT-TMX conjugates [219].…”

Section: ) Hydrogen Ion Dynamics In Multiple Drug Resistance (Mdr) Imentioning

confidence: 99%

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

Harguindey¹,

Alfarouk

Orozco³

et al. 2019

Preprint

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Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success story. The advances in surgery, chemotherapy and radiotherapy have not been sufficient. Indeed, the accumulated experience clearly indicates that new perspectives and non-main stream approaches are needed to better characterize the etiopathogenesis and treatment of this disease. This contibution deals with how the new pH-centric anticancer paradigm plays a fundamental role in reaching a more integral understanding of the etiology, etiopathogenesis and treatment of this multifactorial disease. For the first time the armamentarium available for the treatment of the different types and phases of BC is approached here from a Unitarian perspective based upon the hydrogen ion dynamics of cancer. The wide-ranged pH-related molecular, biochemical and metabolic model is able to embrace most the fields and subfields of breast cancer pathology. This single and integrated approach allows to advance a unidirectional program to treatment. Further efforts in this line are likely to first improve the therapeutics of each subtype of this tumor, then every phase of the disease and finally every individual patient.

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“…18 Unfortunately, patients with ER-negative breast cancer were unresponsive to antiestrogens like tamoxifen. 19,20 Moreover, there still large amounts of patients who failed to respond to tamoxifen therapy or even developed tamoxifen resistance. 21 To overcome these limitations, numerous studies have been turned to explore novel anticancer agents existed in medicinal plants and nutriment for breast cancer prolonged therapy.…”

mentioning

confidence: 99%

“…It should be noted that MDA-MB-231 cells showed less sensitivity to quercetin than that of MCF-7 cells. Moreover, lower concentration slightly promoted cell proliferation of MDA-MB-231 cells but with no significant difference, which were different with that of MCF-7 cells.Since ER-negative breast cancer cells were unresponsive to tamoxifen,19,20 we therefore evaluate the combined effects of tamoxifen (5 μM) and quercetin (5 and 100 μM) on ER-positive MCF-7 cells in the subsequent studies. Herein, the total viability was investigated with CCK-8 and RTCA assays.…”

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confidence: 99%

Quercetin exerts bidirectional regulation effects on the efficacy of tamoxifen in estrogen receptor‐positive breast cancer therapy: An in vitro study

Zhao

Zheng

et al. 2020

Environmental Toxicology

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Tamoxifen was widely applied in the therapy of estrogen receptor (ER)-positive breast cancer. With the purpose of determining the potential impacts of quercetin on its effectiveness, MCF-7 cells were selected as the in vitro model and several cellular biological behaviors (ie, cell proliferation, migration, invasion, cycle, apoptosis, and oxidative stress) were investigated. As results, quercetin showed contrasting doseresponse to cellular behaviors dependent on the ROS-regulated p53 signaling pathways. In detail, quercetin promoted cell proliferation and inhibited cell apoptosis at low concentrations, whereas high-concentration resulted in apoptosis induction. Moreover, quercetin at a low concentration significantly inhibited tamoxifen-induced antiproliferation in MCF-7 cells, whereas high concentrations enhanced cell apoptosis in a synergetic manner. The real-time quantitative polymerase chain reaction analysis further implied that quercetin exerted its dual roles in tamoxifen-induced antiproliferative effects by regulated the gene expression involved in cell metastasis, cycle, and apoptosis through the ER pathways. Our present study provides a considerable support to the combination of quercetin and tamoxifen on human ER-positive breast carcinoma management.

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Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs

Cited by 35 publications

References 46 publications

Melatonin receptor ligands: A pharmaco‐chemical perspective

Melatonin receptor ligands: A pharmaco‐chemical perspective

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

Quercetin exerts bidirectional regulation effects on the efficacy of tamoxifen in estrogen receptor‐positive breast cancer therapy: An in vitro study

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