Ion transport and cell death

Scheme 5.1. Synthetic routes to TPE-based compounds

1.3. Ion transport and cell death

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mM) and Na⁺ (10–30 mM) ions are much lower than their extracellular concentrations (120 and 142 mM, respectively), whereas the intracellular concentration of K⁺ (140 mM) ions is much higher than their extracellular concentration (4 mM). Maintenance of the concentration gradients of these monovalent ions across the bilayers upholds the cell size and regulates the viability of the cells. K⁺ channels are one of the key players of apoptosis, given the fact that the K⁺ ions greatly influence the membrane potential and regulate cell volume in an isotonic environment, which are the hallmarks of apoptosis. Recent studies have reported that the efflux of K⁺ ions and reduced intracellular K⁺ ion concentration induces apoptosis. The activation of caspases and the apoptotic nuclease activity is also responsive to the K⁺ ion concentration; however, once they are activated, the fluctuation of K⁺ ion concentration couldnot control their activity.¹⁷ Other monovalent ions like Na⁺ are also involved in the apoptotic volume decrease, resulting in the degradation of genetic material and, eventually, cell death. However, the efflux of K⁺ ions does not solely guide the influx of Na⁺ ions, suggesting the fact that separate ionic pathways do exist for the K⁺ and Na⁺ ions during apoptosis. The use of saxitoxin, a sodium ion channel blocker, prevents apoptotic cell death exemplifying the fact that the Na⁺ ion not only assists the other monovalent ions in maintaining appropriate ion homeostasis and regulating the cell size, but its concentration also plays a pivotal role in initiating the signals for the apoptotic machinery. The Cl⁻ ion is also highly abundant in all organisms. K⁺ efflux is inseparably related to apoptotic volume decrease (AVD), and it is also demonstrated that to drive the efflux of water, which leads to cell shrinkage, Cl⁻ ion usually follows K⁺ ion efflux, thereby maintaining the charge neutrality of the process. In response to several apoptotic stimuli, various volume-regulated anion channels (VRACs) also get activated, which results in the efflux of Cl⁻ ions in the pre-apoptotic phase. The AVD under normotonic conditions is accompanied by regulatory volume decrease (RVD), which is accomplished with the help of both K⁺ and Cl⁻ channels. Hence, quite expectedly, it was found that blocking the volume regulatory K⁺ and Cl⁻ channels did not allow the cells to show any morphological features characteristic of apoptosis such as caspase activation, cytochrome c release, and DNA laddering, and hence the cells were rescued from cell death.^18-19 The VRACs are also triggered by both cell swelling and increased production of reactive oxygen species (ROS).²⁰ During AVD, these VRACs get activated and instigate a variety of cellular processes, even in non-swollen cells. Pharmacological inhibition of

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these channels leads to the prevention of AVD in many cell types. Several other channel- mediated Cl⁻ flux processes are also involved in apoptosis. The modulation of Cl⁻ flux is reported to damage the intrinsic pathways of apoptosis initiation, whereas it has a negligible effect on the extrinsic pathway of apoptosis. Volume-sensitive outwardly rectifying (VSOR) chloride channels are primarily involved in the transportation of Cl⁻ ions during apoptosis.²¹

Cells have primarily industrialized a defensive mechanism for maintaining cell volume and ion homeostasis across their membranes in response to the changes in ion concentration in the intra- and extracellular environments. Therefore, the deregulation of the natural ion transport system leads to various ion channel-related diseases, including cystic fibrosis and cancer. In this regard, synthetic ion channels and carriers have been developed to combat dysregulated ion transport-related diseases. Recently, several research groups have explored the ion transport properties of synthetic ionophores in the cellular environment.^{6-7, 22-23} Even a few studies have also demonstrated the activities of the synthetic ionophores under in vivo conditions. Although the investigation of ionophore arbitrated biological activities is in its early stage of development, it has tremendous therapeutic potential. The synthetic ionophores showed Cl⁻ ion transport efficiency across the membranes of epithelial cells with functionally faulty CFTR channels. The treatment with the synthetic ionophores also led to the induction of apoptosis in cancer cells. Hence, synthetic ionophores have the potential to fight against cancer, cystic fibrosis, and other ion transport-related diseases. In general, the ionophores are hydrophobic in nature and function within the lipid bilayer, and they do not bind to any bio-macromolecules like DNA, proteins, or enzymes but regulate ion transport to induce apoptosis. In this regard, the synthetic ionophores could overcome the perturbations due to the mutations and over- expression of genetic material and proteins/enzymes and established as an unorthodox approach for numerous pathological conditions. So based on this tremendous applicability to the healthcare system, scientists across the globe have been exploring numerous natural as well as artificial anion transporter molecules and trying to explore their numerous pharmacological efficacy. So within this chapter, several natural product-based anionophores and their biological applications as an anti-proliferative agent are summed up. Besides, numerous artificial anionophores having therapeutic prospects are also discussed.

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