The prevalence of cancer is growing worldwide with millions of deaths every year. We are still trying to fully understand the mechanisms used by malignant cells to avoid growth control. These mechanisms may be the same mechanisms which allow tumor cells to overcome the cytotoxic effects of chemotherapeutic drugs<2>. A fundamental concept in chemotherapy treatment is to target cellular replication mechanisms but this provides only limited efficacy as proliferation rates differ among tumor tissue cells<3>. The undesirable side effects of chemotherapeutic drugs are well known and in many cases induce more adverse effects than inhibition of tumor growth<2>. Administration of Proton Pump Inhibitor's (PPIs) at high doses is currently being investigated as a new class of antitumor agent with a lower level of systemic toxicity. Targeting the tumor microenvironment acknowledges cancer not only as a genetic disease but as a disease where selected phenotypic changes (hallmarks of cancer) and genetic mutations evolve in a complex physical and biochemical microenvironment<4>. These hallmarks are not only related to genetic alterations but also linked to alterations in cancer cell metabolism<4>. Acidity is a common feature of all solid tumors and contributes to drug-resistance and malignant tumor progression making pH homeostasis a feasible target in cancer treatment<3,5>.
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Tumor cells up-regulate glycolysis and grow in an oxygen deficient (hypoxic) environment. Cells which are highly proliferative produce large amounts of hydrogen ions (H+) generated by glycolysis, lactic acid production, glucose utilization and proton efflux<6>. The environment created during tumor growth selects for cells that are able to avoid intracellular accumulation of acids which is achieved through active proton extrusion via proton pumps<3>. The altered glycolytic tumor metabolism results in an alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe) (figure 1). This disrupted pH homeostasis is critical for the survival of the tumor as many cellular biochemical processes have a narrow pH optimum<2>. This reversed pH gradient would quickly kill normal cells which are unable to efficiently extrude H+ out of the cell and sustain an acceptable pH to carry out essential intracellular processes<7>. An acidic pHe enhances the activity and secretion of proteolytic enzymes involved in extracellular matrix degradation (cathepsin B, matrix metalloproteases, gelatinase and collagenase) and has also been shown to increase the metastatic and invasive capacity of breast cancer cells and melanoma<8>. The remodelling and degradation of the extracellular matrix is a characteristic feature of cancer metastasis<9>.
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Figure 1: Tumor cells are characterized by an acidic extracellular pH and relatively alkaline intracellular pH <2>.
The role of V-ATPASE in malignant tumors
There are many pHi regulatory mechanisms at work in tumor cells such as Na+/H+ exchangers, carbonic anhydrases, H+-linked monocarboxylate transporters and proton pumps like the vacuolar ATPase (VATPase) and the F1F0-ATP synthase<3>. When it comes to using PPIs in cancer treatment, the proposed molecular target is V-ATPase<10>. V-ATPase is up-regulated in tumor cells and plays a crucial role to regulate vesicular trafficking in all cells <11>. The use of different ion exchangers may help to distinguish the metastatic behavior of tumor cells<12>. It has been found that highly metastatic breast cancer cells preferentially use V-ATPase's and breast cancer cells with less metastatic potential preferentially use Na+/H+ exchangers and bicarbonate based H+ transporting mechanisms<12>.
Inhibition of V-ATPase function suppresses cancer metastasis by decreasing proton extrusion and down-regulated protease activity<14>. V-ATPase specific inhibitors have been shown to induce apoptosis in human cancer cells but due to their ubiquitous expression, they are highly cytotoxic toward normal cells limiting their clinical use<13>.
Acidity and drug resistance
The mechanisms of drug entry into a cell are dependent on concentration and pH gradients. Thus, malignant tumours which are characterized by reverse pH gradients can affect drug distribution, uptake and activity<15>. Chemotherapeutic drugs that are weakly basic are protonated in the acidic tumor stroma or organelles have decreased uptake by the cells or decreased sequestration and extrusion within acidic vesicles trafficking<16>. On the other hand weakly acidic compounds have an increased activity at acidic pHe <17>. Agents that are able to disrupt/normalize the pH gradient of tumor cells have the potential to improve sensitivity to cytotoxic agents and inhibit tumor growth.
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The rationale behind the use of PPIs is to block H+ efflux and increase tumor pHe which would result in better penetration of weakly basic drugs. PPI's specifically target proton-ATPases within the lumen of gastric parietal cells but they also have the ability to inhibit the activity of V-ATPases and block proton transport across membranes<2>.
The great potential advantage of using PPIs over other agents is that their impact can be tumor specific because they are activated in the acidic extracellular space of tumors<18>. In vivo, high non-toxic doses of PPI's analogous to those used in Zollinger-Ellison syndrome have suppressed the growth of melanoma in nude mice which was associated with a near doubling of survival time<19>. Preclinical data on potential dosing schedules are comparable with those administered to patients with zollinger syndrome who receive up to 240mg/day of esomeprazole for several days with minimal side effects<20>.
Preclinical data suggested that PPIs cause cell death by targeting tumor cells due to their acidic pH, and without targeting any specific tumors. However, further experiments have shown that PPIs may actually induce selective toxicity by inhibiting vital mechanism that allow tumor cells to eliminate protons and reactive oxygen species (ROS) <21>. The accumulation of ROS is an early event in the antineoplastic effect mediated by PPIs and the permeabilization of acidic vesicles is a critical part of the apoptotic cascade<21>. The acidification of the cytosol creates the optimum conditions for massive activation of protease and other lytic enzymes leading to cell death through auto-digestion or cessation of metabolic function<22>.
Thus, PPIs may represent a prototype model of antitumor pro-drugs. They are effectively able to exploit the acidic pHe as a therapeutic target and selective delivery system. PPIs shift the baseline pHe to be more alkaline and reduce the intracellular pH. This has significant consequences on both the ability of malignant cells to survive in acidic conditions and can also enhance the penetration of chemotherapeutic drugs within tumor cells and in the tumor microenvironment. The cell processes and mechanisms which create a reverse pH gradient in tumors may represent a selective and specific target in the future strategies against cancer based on tumor acidity.