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Okorokova‐Façanha, Anna L.; Reis, Michele C.; Montero-Lomelı́, Mónica

doi:10.1023/a:1007147426838

Cited by 14 publications

(3 citation statements)

References 48 publications

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“…At the same time berberine targets Sp1 (specifity protein 1) which is a transcription factor for HIF expression [112]. Sp1 is also one of the promoters of NHE-1 [113]. In spite of all the anti-cancer effects of EVO, it increases IL8 expression and adhesive molecules in gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Re-Purposing Evodiamine as an Anti-Cancer Drug: Effects on Migration and Apoptosis

Koltai¹

2018

OAJOM

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Introduction: Evodiamine is a quinolone alkaloid compound obtained from a fruit described in traditional Chinese medicine. It has been in use for many centuries for the treatment of headaches, menstrual problems, abdominal pain and other ailments. In the western world, it is known as a controversial weight loss product and is sold over the counter as a nutritional supplement. Many freely sold weight loss products contain evodiamine associated with other supposed weight control chemicals. Even though there are no reliable statistics, we may presume that thousands of persons have been using it without serious side effects being reported.Background: At the beginning of this century researchers found that this compound had anti-cancer effects: cytotoxicity and decreased invasion and migration in vitro in malignant cells while showing minimal damage to normal cells. Little has been investigated about in vivo effects on cancer. There is a lack of information regarding the possibility of achieving the clinical concentrations needed for tumour cytotoxicity and for inhibiting migration. Objectives:The goal of this study was to determine the feasibility of re-purposing evodiamine as an anti-cancer drug. For this, we investigated: a. the possibility of achieving the cytotoxic concentrations of the drug required at tumor level in the clinical setting; b. the molecular mechanisms responsible for the anti-cancer effects; c. which types of tumours can be treated; d. its interrelation with other chemotherapeutics; e. Interrelation of evodiamine with berberine in anti-cancer effects. Material and Methods:Due to the abundance of published research on evodiamine, many of the objectives could be accomplished by reviewing the literature, introducing a systematic search, and organizing the findings.Results: The necessary concentrations to achieve possible clinical results may be reached through oral administration. This concept applies mainly to inhibition of migration, that requires a low concentration. The cytotoxic effects need higher concentrations that are not easily attainable with standard preparations. An association with berberine, a non-toxic compound, increases evodiamine's cytotoxicity. Almost all malignancies, whether solid or hematologic, are affected by evodiamine in a dose dependent manner. Evodiamine may also complement the activity of other chemotherapeutics like campthotecin, taxanes, doxoubicin and probably radiotherapy as well. Conclusion:Evodiamine should be tested in humans to establish the achievable plasma concentrations, because all the published pharmacodynamic reports were based on tests on rodents. Whether alone or associated with berberine, evodiamine,deserves to be tested in well designed clinical trials for the treatment of cancer and prevention of metastasis.

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Section: Discussionmentioning

confidence: 99%

Re-Purposing Evodiamine as an Anti-Cancer Drug: Effects on Migration and Apoptosis

Koltai¹

2018

OAJOM

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“…This transcription factor is involved in the regulation of many genes. Interestingly, it induces/ enhances the expression of many of the participants of the pHtome, namely CAIX [126,127], NHE1 [128], NHE2 [129], NHE3 [130], NBC1 [131], and some proton pumps such as H-K-ATPase [132]. Furthermore, Sp1 transcription activity is pH-dependent [133]: low intracellular pH increases Sp1 DNA binding and its interaction with TATA binding protein.…”

Section: (10) Sp1 Transcription Factormentioning

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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“…The promoter region of NHE1 has been cloned and characterized in human, mouse, rabbit, and pig (26, 80, 82, 195), but only the mouse NHE1 promoter was analyzed in more detail. The mouse NHE1 promoter is activated by AP-2-like transcription factors (80), as well as a poly (dA:dT) region of the promoter interacting with an unidentified nuclear protein (325).…”

Section: Regulation Of the Na+/h+ Exchangers Expressed In The Digestimentioning

confidence: 99%

SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

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The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

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Untitled

Cited by 14 publications

References 48 publications

Re-Purposing Evodiamine as an Anti-Cancer Drug: Effects on Migration and Apoptosis

Re-Purposing Evodiamine as an Anti-Cancer Drug: Effects on Migration and Apoptosis

Targeting the pH Paradigm at the Bedside: A Practical Approach

SLC9 Gene Family: Function, Expression, and Regulation

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