FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

Pellegrino, Michele; Rizza, Pietro; Nigro, Alessandra; Ceraldi, Rosangela; Ricci, Elena; Perrotta, Ida; Aquila, Saveria; Lanzino, Marilena; Andò, Sebastiano; Morelli, Catia; Sisci, Diego

doi:10.1158/1541-7786.mcr-17-0662

Cited by 20 publications

(24 citation statements)

References 47 publications

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“…Recently published data from our laboratory suggest that a promising pharmacological candidate for such an adjuvant therapy in patients who result refractory to the antiestrogen treatment is LTG, a well-known AED that is able to increase FoxO3a levels in BCCs [28]. Thus, to evaluate if LTG, by inducing FoxO3a expression, is able to restore the sensitivity to the anti-hormonal therapy also in vivo, female nude mice bearing TamR cells-derived tumor xenografts into the intrascapular region, were treated with LTG (20 mg/kg/day) on the basis of our in vitro results [28] and on the pertinent literature [36].…”

Section: The Aed Lamotrigine Restores the Sensitivity To Tamoxifen Treatment Through Foxo3a Re-expression In Tamoxifen Resistant Xenografmentioning

confidence: 99%

“…In this context, here, we investigated, for the first time, the protective role of FoxO3a in the progression of ER+ BC from a sensitive to a resistant phenotype to tamoxifen treatment. Moreover, since we recently demonstrated that the antiepileptic drug (AED) lamotrigine (LTG), similarly to other AEDs [25][26][27], is able to inhibit BC growth by inducing FoxO3a expression [28], its potential use as adjuvant to tamoxifen therapy has been proposed.…”

Section: Introductionmentioning

confidence: 99%

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FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer

Pellegrino

Rizza

Donà

et al. 2019

Cancers

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Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan–Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan–Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk.

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Section: The Aed Lamotrigine Restores the Sensitivity To Tamoxifen Treatment Through Foxo3a Re-expression In Tamoxifen Resistant Xenografmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer

Pellegrino

Rizza

Donà

et al. 2019

Cancers

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“…Cells were plated as previously described ( Pellegrino et al, 2018 ). After 2 days, vehicle (−) or treatments (OLA at 50 and 100 μM) were added and replaced every 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…Cell lines were acquired and authenticated from Interlab Cell Line Collection (ICLC, Genova, Italy), they were tested monthly for negativity to Mycoplasma (MycoAlert, Lonza) and they were maintained as previously described (Pellegrino et al, 2018).…”

Section: Cell Culturesmentioning

confidence: 99%

Production of Plant-Derived Oleuropein Aglycone by a Combined Membrane Process and Evaluation of Its Breast Anticancer Properties

Mazzei

Piacentini

Nardi

et al. 2020

Front. Bioeng. Biotechnol.

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Natural products and herbal therapies represent a thriving field of research, but methods for the production of plant-derived compounds with a significative biological activity by synthetic methods are required. Conventional commercial production by chemical synthesis or solvent extraction is not yet sustainable and economical because toxic solvents are used, the process involves many steps, and there is generally a low amount of the product produced, which is often mixed with other or similar byproducts. For this reason, alternative, sustainable, greener, and more efficient processes are required. Membrane processes are recognized worldwide as green technologies since they promote waste minimization, material diversity, efficient separation, energy saving, process intensification, and integration. This article describes the production, characterization, and utilization of bioactive compounds derived from renewable waste material (olive leaves) as drug candidates in breast cancer (BC) treatment. In particular, an integrated membrane process [composed by a membrane bioreactor (MBR) and a membrane emulsification (ME) system] was developed to produce a purified non-commercially available phytotherapic compound: the oleuropein aglycone (OLA). This method achieves a 93% conversion of the substrate (oleuropein) and enables the extraction of the compound of interest with 90% efficiency in sustainable conditions. The bioderived compound exercised pro-apoptotic and antiproliferative activities against MDA-MB-231 and Tamoxifen-resistant MCF-7 (MCF-7/TR) cells, suggesting it as a potential agent for the treatment of breast cancer including hormonal resistance therapies.

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“…Most anti-epileptic drugs in clinical use, including phenytoin [191][192][193], carbamazepine [194][195][196][197], lamotrigine [198], topiramate [199][200][201][202], and many others, inhibit VGSCs and show different degrees of anti-tumoral effects (for a review see Koltai [203]). From a long list of VGSC inhibitors, we have chosen topiramate because it has a quadruple action against tumors:…”

Section: Voltage Gated Sodium Channels (Vgscs) Inhibitionmentioning

confidence: 99%

Targeting the pH Paradigm at the Bedside: A Practical Approach

Koltai¹

2020

IJMS

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The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the “cancer problem”? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article’s goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.

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FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

Cited by 20 publications

References 47 publications

FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer

FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer

Production of Plant-Derived Oleuropein Aglycone by a Combined Membrane Process and Evaluation of Its Breast Anticancer Properties

Targeting the pH Paradigm at the Bedside: A Practical Approach

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