“…Early work demonstrated that an acidic pH enhances radiation survival of cells in culture [81] and this was ascribed to reduced fixation of radiation damage [82]. Although an acidic extracellular pH may enhance radiation-induced expression of p53 [83], several studies have shown that low pH ( ∼ 6.5) inhibits or at least delays radiation-induced apoptosis (Table 2) [84][85][86][87][88][89] (also see Fig.…”
Section: Is Radiation-induced Apoptosis Modulated By Ph?mentioning
“…Early work demonstrated that an acidic pH enhances radiation survival of cells in culture [81] and this was ascribed to reduced fixation of radiation damage [82]. Although an acidic extracellular pH may enhance radiation-induced expression of p53 [83], several studies have shown that low pH ( ∼ 6.5) inhibits or at least delays radiation-induced apoptosis (Table 2) [84][85][86][87][88][89] (also see Fig.…”
Section: Is Radiation-induced Apoptosis Modulated By Ph?mentioning
“…The phase of the cell cycle also affects radiation responses, with cells in G2/M and G1 phases the most radiosensitive and those in the S phase more radioresistant [ 91 , 92 ]. Increased acidification decreases the effectiveness of radiation; cells cultured in acidic media are more resistant to radiation, with acidic pH e shown to reduce fixation of radiation-induced DNA damage, inhibit radiation-induced apoptosis, and delay G2/M-phase arrest allowing more time for treated cells to repair DNA damage, thus increasing radioresistance [ 7 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ].…”
Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in both in vitro and in vivo pre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation.
“…Radiotherapy is also inhibited by low extracellular pH (7–9). This is not simply due to reduced numbers of cycling cells, as pH must be reduced after treatment in order to confer resistance (9–11). By contrast, extracellular pH (pHe) sensitizes tumor cells to hyperthermic therapy (12–15).…”
Section: Causes and Consequences Of Tumor Hypoxia And Aciditymentioning
The microenvironment within tumors is significantly different from that in normal tissues. A major difference is seen in the chaotic vasculature of tumors, which results in unbalanced blood supply and significant perfusion heterogeneities. As a consequence, many regions within tumors are transiently or chronically hypoxic. This exacerbates tumor cells' natural tendency to overproduce acids, resulting in very acidic pH values. The hypoxia and acidity of tumors have important consequences for antitumor therapy and can contribute to the progression of tumors to a more aggressive metastatic phenotype. Over the past decade, techniques have emerged that allow the interrogation of the tumor microenvironment with high resolution and molecularly specific probes. Techniques are available to interrogate perfusion, vascular distribution, pH, and pO 2 nondestructively in living tissues with relatively high precision. Studies employing these methods have provided new insights into the causes and consequences of the hostile tumor microenvironment. Furthermore, it is quite exciting that there are emerging techniques that generate tumor image contrast via ill-defined mechanisms. Elucidation of these mechanisms will yield further insights into the tumor microenvironment. This review attempts to identify techniques and their application to tumor biology, with an emphasis on nuclear magnetic resonance (NMR) approaches. Examples are also discussed using electron MR, optical, and radionuclear imaging techniques.
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