The Potential Role of Systemic Buffers in Reducing Intratumoral Extracellular pH and Acid-Mediated Invasion

Abstract

A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO3) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pKa. This indicates that NaHCO3, with a pKa of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pKa of ~7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion.

Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

“…The latter has been successfully applied in mouse models to change the tumor metabolism, thereby reducing aggressiveness and metastasis. 11,12 Our results now suggest that counteracting tumor acidosis by neutralization could unleash an additional tumor-destructive mechanism by helping maintain CTL activity.…”

“…Targeting of select pathways provides an explanation for the observed split inhibition where CTL cytokine response was completely blocked while granule exocytosis was only partly inhibited in lactic acid milieu. The reversibility of CTL inhibition by buffering the extracellular pH of the lactic acid milieu suggests that neutralization of the tumor milieu might not only suppress metastatic capacity, as has been suggested, 11,12 but could also improve the targeting of the tumor by immune effector cells, thereby enhancing the effect of ATT.…”

“…10 Lactic acid and extracellular acidosis have been shown to influence tumor growth, invasion and metastasis. 9,11,12 Interference with signaling cascades, in particular activation of the extracellular signal-regulated kinase (ERK) pathway in tumor cells, has been documented, possibly explaining the association with increased proliferative capacity. 13,14 Effects on different cells of the immune system have also been reported 15,16 ; yet, little is known about the mechanisms by which eCD8-cells are influenced.…”

Investigating Effects of Acidic pH on Proliferation, Invasion and Drug-Induced Apoptosis in Lymphoblastic Leukemia

“…An inevitable consequence of aerobic glycolysis is the production of lactic acid [3,4]. Studies have shown that the extracellular pH of normal cells is in the range of 7.2 to 7.5, whereas the extracellular pH of cancer cells is in the range of 6.2 to 6.9 which is caused by aerobic glycolysis [3][4][5][6].…”

Modulation of autophagic activity by extracellular pH

“…19 Interestingly, recent reports have demonstrated that tumoral acidosis can be reduced by increasing systemic concentrations of pH buffers, inhibition of carbonic anhydrase IX and proton pump, which leads to suppression of malignant growth, suggesting the potential exploitation of the pH environments for the treatment of cancer. 12,[20][21][22][23] Moreover, changes in extracellular pH also play important roles in immune function, bone function and the nervous system.…”