ReviewClassification of mitocans, anti-cancer drugs acting on mitochondria
Introduction
In the post-genomic era of the third millennium biomedical research has witnessed resurgence of ‘yonder-years’ scientific discoveries. It is now clear that some of the processes that were the focus of research decades ago, are now being exploited as potential targets in cancer treatment. Interestingly, the products of the same genes whose mutations can promote malignant transformations are also the emerging targets for novel, thus far largely unexploited anti-cancer agents. For example, the mitochondrial complex II (CII) has recently been described as a new target for anti-cancer drugs (Albayrak et al., 2003, Dong et al., 2008, Dong et al., 2009, Dong et al., 2011a, Dong et al., 2011b, Rohlena et al., 2011). Intriguingly, mutations in the genes coding for its four subunits have been classified as tumour suppressors, since mutation in these genes is positively correlated with the incidence of certain infrequent neoplasias, viz. pheochromocytoma and paraganglioma (Astuti et al., 2001, Burnichon et al., 2010, Gimenez-Roqueplo et al., 2001, Gottlieb and Tomlinson, 2005, Maxwell, 2005, Schiavi et al., 2005). Therefore CII is an example of a target for anti-cancer drugs that, due to mutations in the genes coding its subunits is involved in the mutagenic switch.
Many of the agents with anti-cancer activity that act on mitochondria, mitocans, hold a substantial promise to be developed into efficient anti-cancer drugs, based on their selectivity for cancer cells (Fulda and Kroemer, 2011, Fulda et al., 2010, Kepp et al., 2011, Lemarie and Grimm, 2011, Ralph et al., 2010a, Ralph et al., 2010b, Shoshan-Barmatz and Ben-Hail, 2012, Wallace et al., 2010, Wang et al., 2010). The importance of mitochondria as an emerging and perspective target for anti-cancer agents is corroborated by the recent findings that tumours differ in the level of expression of a high number of genes and mutations even amongst patients with the same type of tumour. This has been documented for pancreatic cancer and glioblastoma multiforme (Jones et al., 2008, Parsons et al., 2008), and, even worse, there are differences in mutations within the same tumour (Gerlinger et al., 2012). These findings are echoed in the sombre-sounding editorial in Nature titled ‘Cancer complexity slows quest for cure’ (Hayden, 2008). This indicates that it will be unlikely to suppress cancer by targeting a single gene or a single pathway that may alter amongst cancer patients and that can be subject to mutations. Rather, it is imperative to search for a target that is invariant and whose exploitation may present a general strategy for efficient treatment across the landscape of neoplastic pathologies.
It appears clear that such a target is represented by mitochondria that are, at least to some extent, functional in the vast majority if not all cancers (Ralph et al., 2010a, Ralph et al., 2010b). Mitochondria, whilst being the ‘powerhouse’ of the cell, are also reservoirs of a number of apoptosis-promoting proteins that are essential for apoptosis induction and its progression downstream of these organelles, in order for the cancer cell to go into the commitment phase and undergo the final demise (Galluzzi et al., 2010, Kroemer et al., 2007). It is also important to take into consideration the aberrant mitochondrial metabolism in malignant cells (Koppenol et al., 2011, Ward and Thompson, 2012). Thus, the recent decade or so has witnessed an unprecedented focus and discovery of novel agents that target mitochondria to induce cancer cell death. In some cases, ‘old’ compounds have been re-discovered for their propensity to destabilise mitochondria and kill cancer cells. Similarly and with an undisputable involvement in the molecular mechanism of the mitochondria-targeting anti-cancer agents, the Warburg's hypothesis published in the 1920s (Warburg, 1956) has been recently experiencing a renaissance of sorts (Cairns et al., 2011, Hanahan and Weinberg, 2000, Hanahan and Weinberg, 2011, Koppenol et al., 2011, Vander Heiden et al., 2009).
The paramount importance of discovering novel and efficient anti-cancer agents is even more accentuated by the fact that neoplastic diseases are now the greatest threat to the Western society and are likely to increase in frequency (Jemal et al., 2011, Siegel et al., 2012, Simard et al., in press). We believe that targeting mitochondria, for tumour treatment may lead to a potential future breakthrough in the management of malignancies. In this review, we propose the classification of anti-cancer agents that act via mitochondrial destabilisation (mitocans, an acronym for ‘mitochondria and cancer’) and provide several examples epitomising the individual classes of mitocans, in particular those that are perceived as clinically relevant anti-cancer agents. The classification is based on the site of action of the individual agents from the surface of the mitochondrial outer membrane (MOM) to the mitochondrial matrix. The selection of the sites also stems from their importance as targets for the development of drugs that hold substantial promise to be utilised in the clinical practice.
Section snippets
Class 1 mitocans: hexokinase inhibitors
This class of agents comprises compounds targeting hexokinase (HK), which is an enzyme whose main role is to phosphorylate glucose converting it to glucose-6-phosphate (G6P), a substrate for metabolic pathways ultimately coupled with ATP generation. HK has a very important function in cancer. Besides converting glucose to G6P, which can then enter the metabolic machinery to, ultimately, yield ATP, HK is associated with the cytosolic site of the porin-like voltage-dependent anionic channel
Class 2 mitocans: compounds targeting Bcl-2 family proteins
This class of mitocans includes compounds acting as mimetics of the Bcl-2 homology-3 (BH3) domains, integral parts of Bcl-2 family of proteins. When the levels of expression of the pro-apoptotic members of the family are greater, the cell will undergo the demise, whereas higher levels of expression of the anti-apoptotic Bcl-2 family proteins will provide a pro-survival ‘environment’. Although recent findings revealed novel functions for the Bcl-2 family members, including a role in the
Classes 3 and 4 of mitocans: thiol redox inhibitors plus VDAC/ANT targeting drugs
Classes 3 and 4 comprise thiol redox inhibitors and the VDAC/ANT targeting drugs, and their activity is linked to the redox environment of cancer cells, which is distinct from that of normal cells in that cancer cells show higher intrinsic levels of ROS. As a result, it makes cancer cells more vulnerable to agents that induce further elevations in oxidative stress, since their anti-oxidant capacity is relatively inferior (Huang et al., 2000, Szatrowski and Nathan, 1991). Therefore, compounds
Class 5 mitocans: electron redox chain targeting drugs
Class 5 mitocans comprises a large group of different compounds that target the mitochondrial complexes, a part of the ETC (Scheffler, 2008). Some of them were discussed in recent reviews (Fulda et al., 2010, Galluzzi et al., 2010, Gogvadze et al., 2009, Ralph and Neuzil, 2009, Wang et al., 2010).
The production of energy is achieved by transporting electrons in a coordinated manner from NADH or FADH2 (generated from substrates in the TCA cycle) to the final acceptor, molecular oxygen, to
Class 6 mitocans: lipophilic cations targeting the inner membrane
The molecular target of lipophilic cations acting on the MIM is given by the relatively high trans-membrane potential (ΔΨm,i) that exists across the MIM. It has been documented that cancer cells have a considerably higher ΔΨm,i than non-malignant cells due to altered mitochondrial bioenergetics (Modica-Napolitano and Aprille, 1997). This feature will dictate the intracellular targeting of lipophilic cations that as a result of the increased ΔΨm,i in cancer cells will make these mitocans
Class 7 mitocans: drugs targeting the tricarboxylic acid cycle
The tricarboxylic acid (TCA) cycle, also referred to as the citric acid cycle or Kreb's cycle, is a source of electrons that are fed into the ETC and that are used to drive the electrochemical proton gradient required for the generation of ATP and is the target of class 7 mitocans. The TCA cycle is based on the addition of acetyl-CoA (formed in the mitochondrial matrix) by the conversion of pyruvate (catalysed by pyruvate dehydrogenase) to oxaloacetate to form citrate. Citric acid is then in a
Class 8 mitocans: drugs targeting mtDNA
Group 8 of mitocans comprises agents targeting mitochondrial DNA (mtDNA). Mitochondria are unique organelles because they carry their own genetic information encoded on a small circular genome, referred to as mitochondrial DNA (mtDNA). The mammalian mitochondrial genome has the size of over 16 kB, and encodes 13 subunits of the mitochondrial complexes I, III, IV and V, 24 tRNAs, 12S and 16S rRNA, and also contains a region called the D-loop sequence, which is important in the regulation of mtDNA
Conclusions and future perspectives: clinical relevance of mitocans
Mitocans are, in quite a few cases, selective for cancer cells, which is a prerequisite for a potentially clinically relevant anti-cancer agent. Except for a few compounds, mitocans have not been employed in the clinical setting. One of these exceptions is tamoxifen, one of the most frequently used drugs against breast cancer, which is now also used as a preventive agent, albeit thus far largely due to its effect on the ER, competing with its activating ligand estradiol (Cuzick et al., 2011,
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