**4. Ion channels and transporters with clinical relevance in hematologic malignancies**

As reported for solid tumors, a schematic overview of ion channels and transporters expressed in hematologic tumors is reported in **Figure 2**. Early evidence for the implication of K+ channels in leukemia cell proliferation was obtained in the myeloblastic leukemia cell line ML-1 [128]. In leukemias, it was shown that **KCa3.1** might represent a useful target since its blockade impairs leukemic cells proliferation [129] while *KCNN4* overexpression was detected in follicular lymphomas [130]. A significant **Kv10.1** expression was detected in myelodysplastic syndromes, CML and almost half of a cohort of AML samples and blocking the channel results in the inhibition of both cell proliferation and migration. Smith

**51**

**antibodies**

**Figure 2.**

*Ion Channels and Transporters as Cancer Biomarkers and Targets for Diagnostics with Antibodies*

and colleagues [131] carried out an extensive study of the K+ channel transcripts in primary lymphocytes, leukemias (B-cell CLL) and several leukemic cell lines and they found only *Kv11.1* was significantly up-regulated. In AML cell lines (FLG 29.1, HL-60 and K562), it was shown that specific block of IKv11.1 led to G1 arrest and impaired their migration on fibronectin-containing ECM [132]. Kv11.1 was also overexpressed in circulating blasts from human AML, in which the block of the channel significantly decreased cell growth [132]. The *hsloBK* splice variant of *gBK* has been detected in gliomas [133] and the *herg1b* alternative transcript of *Kv11.1* is overexpressed in human leukemias and neuroblastomas [134, 135]. TWIK-related spinal cord K+ (**TRESK**) channels, members of the double-pore domain K+ channel family, are expressed in Jurkat cells [136] that also express TRPV5 and TRPV6, which were also detected in K562 cells. TRP channels control Ca2+ homeostasis in the context of malignant transformation [137] and it was shown that of TRPV5/ TRPV6-like channels' activation mediate Ca2+ entry and the activation of Ca2+/

During the oxidative burst following activation of K562 cells non-selective cation channel TRPM2 are activated, thus activating **SK4** KCa channels. In parallel, the voltage-gated Cl-channel **ClC-3** is also activated. The overall effect is cell shrinkage because of the osmotic water loss determined KCl outflow [139, 140]. A similar volume-dependent regulation of leukemia cell apoptosis can be operated by volume-regulated chloride currents (**VRCC**). The volume-dependent regulatory mechanisms are accompanied by control of water levels suggesting it could represent an additional modulatory mechanism in the apoptotic cascade [141]. AQPs control osmotic fluxes in a variety of physiological conditions. For instance, AQP5 is overexpressed in CML cells, where it promotes cell proliferation and inhibits apoptosis, perhaps through an effect on cell volume control [142]. Expression of AQP5 increases in parallel with the development of resistance to imatinib mesylate [142].

**5. Targeting ion channels and transporters for cancer diagnosis with** 

Recently, an antibody directed to a cancer-related ion channel (the purinergic receptor P2X7) was introduced into the clinical settings: it is a polyclonal antibody targeting a conformational epitope of the non-functional channel and it is likely

Calmodulin-dependent kinase II in irradiated K562 cells [138].

*Cartoon showing the main ICTs expressed in leukemias and lymphomas.*

*DOI: http://dx.doi.org/10.5772/intechopen.90401*

*Ion Channels and Transporters as Cancer Biomarkers and Targets for Diagnostics with Antibodies DOI: http://dx.doi.org/10.5772/intechopen.90401*

**Figure 2.** *Cartoon showing the main ICTs expressed in leukemias and lymphomas.*

and colleagues [131] carried out an extensive study of the K+ channel transcripts in primary lymphocytes, leukemias (B-cell CLL) and several leukemic cell lines and they found only *Kv11.1* was significantly up-regulated. In AML cell lines (FLG 29.1, HL-60 and K562), it was shown that specific block of IKv11.1 led to G1 arrest and impaired their migration on fibronectin-containing ECM [132]. Kv11.1 was also overexpressed in circulating blasts from human AML, in which the block of the channel significantly decreased cell growth [132]. The *hsloBK* splice variant of *gBK* has been detected in gliomas [133] and the *herg1b* alternative transcript of *Kv11.1* is overexpressed in human leukemias and neuroblastomas [134, 135]. TWIK-related spinal cord K+ (**TRESK**) channels, members of the double-pore domain K+ channel family, are expressed in Jurkat cells [136] that also express TRPV5 and TRPV6, which were also detected in K562 cells. TRP channels control Ca2+ homeostasis in the context of malignant transformation [137] and it was shown that of TRPV5/ TRPV6-like channels' activation mediate Ca2+ entry and the activation of Ca2+/ Calmodulin-dependent kinase II in irradiated K562 cells [138].

During the oxidative burst following activation of K562 cells non-selective cation channel TRPM2 are activated, thus activating **SK4** KCa channels. In parallel, the voltage-gated Cl-channel **ClC-3** is also activated. The overall effect is cell shrinkage because of the osmotic water loss determined KCl outflow [139, 140]. A similar volume-dependent regulation of leukemia cell apoptosis can be operated by volume-regulated chloride currents (**VRCC**). The volume-dependent regulatory mechanisms are accompanied by control of water levels suggesting it could represent an additional modulatory mechanism in the apoptotic cascade [141]. AQPs control osmotic fluxes in a variety of physiological conditions. For instance, AQP5 is overexpressed in CML cells, where it promotes cell proliferation and inhibits apoptosis, perhaps through an effect on cell volume control [142]. Expression of AQP5 increases in parallel with the development of resistance to imatinib mesylate [142].
