The relationship between thermosensitivity and intracellular pH in cells deficient in antiport function

Liu, Fei‐Fei; Diep, Kim; Hill, Richard P.

doi:10.1016/0167-8140(96)01733-1

Cited by 13 publications

(6 citation statements)

References 21 publications

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“…Recently, there has been a renewed interest in treating tumurs with hyperthermia (http://www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia and more than 60 papers in 2011) and there is a group of studies showing that the lowering of pHi (almost all by targeting the NHE1) can strongly enhance the thermosensitivity of the cancer cell [151][152][153][154][155]. Therefore, there are very real and important future possibilities for the combined use of proton transporter inhibitors together with hyperthermia.…”

Section: Hyperthermic Therapy and Phi/nhe1mentioning

confidence: 99%

Na+-H+ Exchanger, pH Regulation and Cancer

Reshkin

Cardone²,

Harguindey³

2012

PRA

131

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Cancer cells and tissues, regardless of their origin and genetic background, have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the intracellular to extracellular pH gradient (pHi to pHe) in cancer cells and tissue as compared to normal tissue. This perturbation in pH dynamics rises very early in carcinogenesis and is one of the most common patho-physiological hallmarks of tumors. Recently, there has been a very large increase in our knowledge of the importance and roles of pHi and pHe in developing and driving a series of tumor hallmarks. This reversed proton gradient is driven by a series of proton export mechanisms that underlie the initiation and progression of the neoplastic process. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na + /H + exchanger isoform 1 (NHE1). The NHE1 is an integral membrane transport protein involved in regulating pH and in tumor cells is a major contributor to the production and maintenance of their reversed proton gradient. It is activated during oncogene-dependent transformation resulting in cytosolic alkalinization which then drives subsequent hallmark behaviors including growth factor-and substrate-independent growth, and glycolytic metabolism. It is further activated by various growth factors, hormone, the metabolic microenvironment (low serum, acidic pHe and hypoxia) or by ECM receptor activation. This review will present the recent progress in understanding the role the NHE1 in determining tumor progression and invadopodia-guided invasion/metastasis and recent patents for NHE1 inhibitors and novel therapeutic protocols for anti-NHE1 pharmacological approaches. These may represent a real possibility to open up new avenues for widespread and efficient treatments against cancer.

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Section: Hyperthermic Therapy and Phi/nhe1mentioning

confidence: 99%

Na+-H+ Exchanger, pH Regulation and Cancer

Reshkin

Cardone²,

Harguindey³

2012

PRA

131

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“…It is thought that the low pH e of tumours potentiates amiloride's tumour selectivity by increasing the active NHE‐inhibiting protonated acylguanidinium form of the drug in the local tumour environment 29. Some reports indicate that NHE inhibition and cytoplasmic acidification with amiloride and its analogues increase the thermosensitivity of tumour cells relative to normal cells 36–38. When tested against SCK mammary adenocarcinoma cells, amiloride, EIPA and HMA each showed enhanced tumour cell killing at 43°C in pH 6.6 media 39.…”

Section: Anti‐tumour and Anti‐metastasis Effects Of Amiloride Via Inhmentioning

confidence: 99%

Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

Matthews

Ranson

Kelso

2011

Intl Journal of Cancer

122

108

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Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This minireview summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs.Amiloride.HCl is an orally administered potassium-sparing diuretic that has been used clinically for more than three decades. Ironically, its principal clinical use is not as a diuretic per se, since its diuretic effects are relatively mild. It is instead more commonly used in combination with thiazide (e.g., hydrochlorothiazide) or loop diuretics (e.g., frusemide) as an antikaliuretic in patients at risk of hypokalaemia during longterm treatment of hepatic cirrhosis and heart failure. It is also frequently used in combination with other diuretics to control K þ -levels when treating hypertension. 1 The drug is usually well tolerated at normal doses, shows low incidence of side effects and is contraindicated only in patients with impaired renal function, hyperkalaemia or acidosis. Hyperkalaemia and associated arrhythmias are the drug's most serious side effects but when used in combination with thiazide diuretics, the incidence of these is <1-2%. 2 Soon after its discovery, amiloride found additional nonclinical uses as a pharmacological tool for probing sodium transport in many types of tissues and cells-uses which continue to this day. 3 Multiple studies over the past three decades have demonstrated that amiloride also exhibits significant anti-tumour and anti-metastasis activities in biochemical, cellular and animal tumour models. This mini-review begins by summarising the reported anti-cancer activities of amiloride in experimental models, discusses its purported anti-cancer mechanisms of action and concludes by commenting on the possibility that amiloride or a close structural analogue might be worth trialling clinically as an orally administered anticancer drug, either as a stand-alone agent or in combination with current chemotherapeutics. Anti-Tumour and Anti-Metastasis Effects of Amiloride in Experimental ModelsReports of in vivo anti-tumour properties for amiloride first appeared in 1983 when it was shown to inhibit H6 hepatoma growth and DMA/J mammary adenocarcinoma growth in a dose-dependent fashion in Male A/J mice. Multiple injections (1 mg/kg) of ...

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“…Details of the clonogenic assay have also been provided previously, 20,22 but in brief, MCF-7, MDA-468, or MCF-10A cells were seeded in 25 cm 2 T-flask (Falcon, Franklin Lakes, NJ) and infected as described above. The cells were infected with 25 PFU/cell adv.AAA or adv.b-gal for 1 hour, and 5 ml of a-MEM containing 10% FBS or 5 ml of 5% HS growth medium was added and further incubated for an additional 24 hours.…”

Section: Clonogenic Assaymentioning

confidence: 99%

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

Szmitko

Brade

et al. 2003

Cancer Gene Ther

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We have previously demonstrated that protein kinase B (PKB) is a mediator of heat-induced apoptosis for human breast cancer cells. To investigate the therapeutic potential of abrogating the function of this important survival protein, a novel replication-deficient adenovirus was constructed, wherein a mutant, kinase-inactive PKB gene (AAA) was inserted downstream of the CMV promoter. Two human breast cancer cell lines, MCF-7 and MDA-468, were treated, along with the MCF-10 serving as a ''normal'' mammary epithelial comparator. Apoptosis was increased with adv.AAA (25 PFU/cell) infection alone, but was significantly enhanced with the addition of heat exposure. Differential survival was observed with the MDA-468 cancer cells being more sensitive than the MCF-7 cells. The MCF-10 cells, in contrast, were most resistant to these treatments. Results from the clonogenic assay reflected the apoptosis data, with an apparent additive interaction between adv.AAA and hyperthermia treatments, again with greater differential sensitivity of the malignant, compared to the ''normal'' mammary epithelial cells. Heat or adv.b-gal treatments led to phosphorylation of PKB and Forkhead, but this phosphorylation was reduced with adv.AAA therapy. In parallel, the combination of adv.AAA and heat treatment reduced PKB kinase activity more so than with either heat or adv.b-gal alone. In conclusion, our results demonstrate that inhibition of the PKB-dependent survival pathway will promote apoptosis and thermosensitization in malignant breast cancer cells, with relative sparing of their normal counterpart, suggesting that a therapeutic gain could be achievable using this therapeutic strategy.

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The relationship between thermosensitivity and intracellular pH in cells deficient in antiport function

Cited by 13 publications

References 21 publications

Na+-H+ Exchanger, pH Regulation and Cancer

Na+-H+ Exchanger, pH Regulation and Cancer

Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

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