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Proton pump inhibitors for the treatment of cancer in companion animals.

Walsh M, Fais S, Spugnini EP, Harguindey S, Abu Izneid T, Scacco L, Williams P, Allegrucci C, Rauch C, Omran Z - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects.A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell.The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, LE12 5RD, UK. Megan.walsh@nottingham.ac.uk.

ABSTRACT
The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.

No MeSH data available.


Related in: MedlinePlus

a Chemical structure of FDA-approved PPIs. b Mechanism of action of PPIs
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Fig2: a Chemical structure of FDA-approved PPIs. b Mechanism of action of PPIs

Mentions: Proton pump inhibitors (PPIs) are the treatment of choice for acid-related disorders. Omeprazole was the first PPI to be approved by the FDA in 1989 to treat heartburn and other symptoms associated with gastroesophageal reflux disease in humans. FDA approved five more PPIs since then, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole. The last two drugs are enantiomers of omeprazole and lansoprazole, respectively (Fig. 2a) [35]. PPIs are acid-activated prodrugs [36]: since PPIs are weak bases (pKa1 = 3.8-4.9), they are only accumulated in acidic tissues such as parietal cells where the pH can go as low as 1. The concentration of PPIs at the luminal surface of the pump is roughly 1000-fold higher than their concentration in the blood. This selective accumulation of PPIs is largely the reason for their high therapeutic index. Mechanistically, the protonation of the pyridine moiety of PPIs initiates a series of reaction leading to the formation of a sulfenic acid and sulfenamide. The latters are highly reactive thiophilic species which will react covalently with different ATPase cysteines to form stable disulfides, thus inhibiting the acid secretion (Fig. 2b) [37, 38].Fig. 2


Proton pump inhibitors for the treatment of cancer in companion animals.

Walsh M, Fais S, Spugnini EP, Harguindey S, Abu Izneid T, Scacco L, Williams P, Allegrucci C, Rauch C, Omran Z - J. Exp. Clin. Cancer Res. (2015)

a Chemical structure of FDA-approved PPIs. b Mechanism of action of PPIs
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559889&req=5

Fig2: a Chemical structure of FDA-approved PPIs. b Mechanism of action of PPIs
Mentions: Proton pump inhibitors (PPIs) are the treatment of choice for acid-related disorders. Omeprazole was the first PPI to be approved by the FDA in 1989 to treat heartburn and other symptoms associated with gastroesophageal reflux disease in humans. FDA approved five more PPIs since then, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole. The last two drugs are enantiomers of omeprazole and lansoprazole, respectively (Fig. 2a) [35]. PPIs are acid-activated prodrugs [36]: since PPIs are weak bases (pKa1 = 3.8-4.9), they are only accumulated in acidic tissues such as parietal cells where the pH can go as low as 1. The concentration of PPIs at the luminal surface of the pump is roughly 1000-fold higher than their concentration in the blood. This selective accumulation of PPIs is largely the reason for their high therapeutic index. Mechanistically, the protonation of the pyridine moiety of PPIs initiates a series of reaction leading to the formation of a sulfenic acid and sulfenamide. The latters are highly reactive thiophilic species which will react covalently with different ATPase cysteines to form stable disulfides, thus inhibiting the acid secretion (Fig. 2b) [37, 38].Fig. 2

Bottom Line: Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects.A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell.The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, LE12 5RD, UK. Megan.walsh@nottingham.ac.uk.

ABSTRACT
The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.

No MeSH data available.


Related in: MedlinePlus