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Radiotherapy, either in the form of external beam radiotherapy or brachytherapy, still represents a key therapeutic option for localized or locally advanced prostate cancers.

The effectiveness of radiotherapy is strongly influenced by the occurrence of adverse effects on surrounding normal tissues, ranging from radiation-induced cystitis and/or proctitis, up to erectile dysfunction (Stewart et al. 2011; Barreto-Andrade et al. 2011).

This acute and chronic by-stander toxicity has been greatly reduced with the introduction of the intensity-modulated radiation therapy (IMRT), which allows a more specific targeting of the tumor area.

Despite the advances in radiotherapy techniques (Esgueva et al. 2012; Meng et al. 2005) up to 30 % of radio-treated (Pollack et al. 2003) (intermediate and high risk Zelefsky et al. 2006; Bill-Axelson et al. 2005) prostate cancer patients experience a very aggressive, metastatic disease (Esgueva et al. 2012).

Radioresistance of PC cells is thought to be due to complex inter-relationships between intrinsic genetic and micro-environmental factors (Bristow and Hill 1998; Bristow et al. 2007).

This scenario is further complicated by the significant variability in normal tissue reactions to the radiation-induced DNA damage among prostate cancer patients.

Ionizing radiation kills eukaryotic cells mainly through the induction of DNA- double-strand breaks (DNA-DSBs) (Ward 1988) and, with a lesser extent, (Bristow et al. 2007) via DNA single-strand breaks (DNA-SSBs), alteration/loss of DNA bases or DNA-DNA/DNA-protein cross-links (Chalmers et al. 2010).

The ratio of SSBs and DSBs generated by therapeutic ionizing radiation is about 25:1, but DNA double-strand breaks (DSBs) are by far the most potent inducers of cancer cell death (Chalmers et al. 2010).

DNA damage detection and repair require several well-characterized epigenetic events, represented, in first instance, by the relaxation of chromatin and phosphorylation of histone H2AX on the chromatin area lining the DNA lesions, followed either by methylation/acetylation, depending on the specific damaged residue (Escargueil et al. 2008).

DSBs result from the collision of base damage or SSBs with the advancing replication fork, and represent the most cytotoxic lesions (Curtin 2012).

They are usually repaired through two interacting pathways: the homologous recombination (HR) and the non-homologous end joining (NHEJ)-one.

HR utilizes the undamaged sister chromatid (or chromosomal homologue) as a template (Sonoda et al. 2006). This means that HR can take place only in S and G2 phases (Bertrand and Saintigny 2004) operating then during DNA replication (Bernstein et al. 2002; Hansen and Kelly 2000; Hoeijmakers 2001).

NHEJ rapidly binds directly to broken DNA ends during all phases of the cell cycle (Weterings and van Gent 2004; Collis et al. 2005; Riballo et al. 2004; Fan et al. 2004; Rothkamm et al. 2003; Willers et al. 2004) but it lacks the ability to restore any DNA that is lost during the breakage event or subsequent processing, thus resulting in error prone (Sonoda et al. 2006; Chalmers et al. 2010).

These two DNA repair pathways are hyper-activated in normal cells in response to radiation-induced DNA damage (Bromfield et al. 2003).

The non-repair or mis-repair of radiotherapy-induced DNA-DSBs, due to the inhibition of HR or NHEJ, leads to chromosomal deletions, translocations and rearrangements (Bertrand et al. 2004; Bindra and Glazer 2005; Guirouilh-Barbat et al. 2004; Richardson et al. 2004), favouring the onset of genetic instability (Collis et al. 2005; Weterings and van Gent 2004) DNA-DSBs repair has been found to be defective in prostate cancer cell lines (Yuan et al. 1999; Collis et al. 2002; Trzeciak et al. 2004; Fan et al. 2004).

Furthermore, models of prostate carcinogenesis have shown the association with increased levels of chromosomal aberrations and instability can drive the progression from high-grade PIN to PC (Elliott and Jasin 2002; Pihan et al. 2001; Vukovic et al. 2003). Accumulating evidences indicate that the defective DNA double-strand break repair could be considered as part of the “mutator” phenotype of PC cells (Loeb et al. 2003; Bristow et al. 2007).

This has particular relevance, if we consider that the fractionated prostate radiotherapy protocols lead to the generation of a huge number of DNA-DSBs.

During the last few years, in order to overcome PC aggressiveness and radioresistance (Overgaard 2007; Wouters et al. 2002), in fact a positive trend toward multiple promising kinds of “combined” therapeutic approaches has been registered.

Intriguing therapeutic approaches to radiosensitize hypoxic, metastasizing and highly lethal PC cells are focusing on the concept of “synthetic lethality”. This definition refers to a situation where the simultaneous presence of two genes mutation results in cell death, whereas each mutation per se does not impair cell viability (Curtin 2012).

This phenomenon has inspired new fascinating chances for cancer treatment.

The most promising clinical translations of synthetic lethality concern cancers with specific defects in the HR-mediated repair of double-strand breaks (Antonarakis and Armstrong 2011), as the tumor suppressors BRCA1 and BRCA2 mutant, hereditary breast or ovarian cancers (Venkitaraman 2002).

These tumors represent the first successful examples of treatments based on the use of a single inhibitor of a DNA repair enzyme to selectively kill tumor cells with a second complementary DNA repair pathway defect (Fong et al. 2009; Bryant et al. 2005).

The absolute requirement of HR for DSB repair results in an extreme dependency of BRCA-mutated tumors on PARP-1 action and BER to maintain genomic integrity (Chalmers et al. 2010; Saleh-Gohari et al. 2005).

PARP-1 is the prototypical member of the “poly(ADP-ribose) polymerases (PARPs) superfamily”, highly active in protecting cells from endogenous and/or therapeutically induced DNA damage (Curtin 2012).

This large family of enzymes is characterized by the “PARP signature” (GenBank XP_037275 residues 796–1014 de Murcia and Ménissier de Murcia 1994): a 50-amino acid sequence within the enzymatic domain, which catalyzes the cleavage of NAD + into nicotinamide and ADP-ribose. This latter is used to synthesize long, branching, negatively charged polymers, which are then covalently attached to a variety of partner nuclear proteins, as core histones, linker histone H1 (Giner et al. 1992; Grube et al. 1991), HMG proteins, topoisomerases I and II, DNA helicases, single-strandbreak repair (SSBR) and base-excision repair (BER) factors, various transcription factors and PARP-1 itself, involved in DNA damage signalling and repair (Pleschke et al. 2000; Ruf et al. 1996; Oliver et al. 2004), proximally to the DNA breaks.

This poly(ADP-ribosyl)ation leads to the loosening of chromatin structure (Schreiber et al. 2006) allowing the spatial organization of DNA repair through the exposure to the cellular DNA repair machinery (Grube et al. 1991).

PARP-1 is a 113-kDa nuclear protein that accounts for at least 80 % of human cellular PARP activity. It is a highly conserved, multifunctional enzyme (Schreiber et al. 2006), with a modular structure (Pfieffer et al. 1999). Under normal conditions, PARP-1 is found associated with histones, DNA and other chromatin associated factors.

In response to DNA damage, it acts as a molecular sensor for DNA-breaks through two zinc-finger motifs, referred to as zf-PARP (Tulin et al. 2002; Menissier et al. 1997), undergoing conformational change and becoming activated.

The binding to DNA breaks, either single-strand break (SSB) and double-strand break (DSB), rapidly stimulated its catalytic activity more than 500-fold. PARP1, as well as his isoenzyme PARP2, acts in SSBs repair mostly by activating base-excision repair (BER).

PARP-1–deficient (or inhibited) cells show, in fact, reduced BER activity (Dantzer et al. 2000) and hypersensitivity to SSB-inducing agents (Horton and Wilson 2007).

If PARP-1 fails to promote SSBs repair, replication forks collapse, converting the DNA damage into replication-associated DSBs, which PARP-1 and PARP-2 attempt to repair either via HR and NHEJ (Chalmers et al. 2010).

The success of PARPs action is strictly dependent upon the extent of the DNA damage. This is due to the transient action of PARP-1 and 2, caused by the rapid degradation of poly-ADP chains due to the poly(ADP-ribose) glycohydrolase (D’Amours et al. 1999).

The half-life of polyADPribose ranges from seconds to minutes, and the hyperactivation of PARP1 consumes the cell pool of NAD + to generate pADPr, lowering cellular energy. So, low-to-moderate DNA damage triggers polyADPribose-dependent DNA repair (Rouleau et al. 2010).

As a complementary effect, pADPr diminishes the affinity for DNA of PARP1, which is then removed from DNA, favouring the post-repair chromatin compaction (Timinszky et al. 2009; Ogata et al. 1980).

In case of excessive DNA damage, PARP1 hyperactivation leads to the excessive NAD + consumption (Juarez-Salinas et al. 1979; Berger et al. 1986; Carson et al. 1988), inducing the catastrophic events that trigger cell death through mechanisms ranging from parthanatos (David et al. 2009; Andrabi et al. 2006), which is directly driven by the longest pADPr chains, to necrosis (Berger et al. 1986; Carson et al. 1988; Zong et al. 2004) or to the establishment of an autophagic state (Huang et al. 2009; Huang and Shen 2009; Munoz-Gamez et al. 2009) of damaged cells.

Due to its fundamental role in DNA-repair, PARP-1 has been identified as the ideal therapeutic target to either specifically kill cancer cells lacking HRR function, and increase the efficacy of radio/chemotherapy in terms of selective tumor cytotoxicity (Farmer et al. 2005; Bryant et al. 2005).

Consistently with these postulates, PARP inhibition in (Bryant et al. 2005) BRCA1 and/or BRCA2-mutated cancer cell (Antonarakis and Armstrong 2011) leads to accumulation of single-strand DNA breaks and (Chalmers et al. 2010) impairs the efficient resolution of collapsed replication forks, impeding the release of PARP molecules from damaged sites, leading to double-strand DNA breaks at replication forks (Antonarakis and Armstrong 2011).

The result is chromosomal instability, cell cycle arrest and subsequent apoptosis caused by the persistence of DNA lesions (Bryant et al. 2005). In other words, the synthetic lethality has been reached.

This synthetic lethality approach has been validated in a multitude of preclinical models, in vitro and in vivo (Bryant et al. 2005; Farmer et al. 2005), and several PARP inhibitors (olaparib-AZD2281, 3-AB, ISQ, NU1025, KU0058684 or AG14361) have shown promising results, when used as single-agents against BRCA1- or BRCA2-mutant tumors in clinical testing (Carnell et al. 2006), and promises, as radio-sensitizers in these tumors (Bristow et al. 2007). However, BRCA2 and BRCA1 germ-line mutation carriers have a higher risk to develop PC respect to the normal population. Respectively, prostate cancer relative risk ranges from 2.5 to 7.5 in BRCA2-mutated and <2.0 in BRCA1-carriers; a data particularly significant in tumors diagnosed in younger patients (between ages 40 and 45) (Dong 2006; Levy-Lahad and Friedman 2007).

However, these subsets of PC are relatively poorly differentiated, with poor prognosis (Horsburgh et al. 2005). Additionally, a new BRCA2-interacting protein, PALB2, has been found to be associated with an increased risk of prostate cancer (Erkko et al. 2007).

Olaparib was the first PARP inhibitor to reach human clinical testing in patients with BRCA1/2-mutated tumors. In a phase I study, oral olaparib allowed a >50 % PSA drop with resolution of bone metastases in a man with BRCA2-related CRPC (Antonarakis and Armstrong 2011). Nevertheless, BRCA1 and BRCA2 mutations are not considered a major cause of familial or sporadic prostate cancer. A number of other mutations that decrease HR and NHEJ DNA repair responses, that can also sensitize PC cells for synthetic lethality induced by PARP inhibitors, are in fact being increasingly detected (Barreto-Andrade et al. 2011; Plummer et al. 2008; Miknyoczki et al. 2003; Calabrese et al. 2003). They include the phosphatase and tensin homolog gene (PTEN) that is located on chromosome 10, frequently deleted in human cancers and commonly inactivated in prostate cancer (Delaney et al. 2000).

PTEN is a tumor suppressor which, besides inactivating the P13-K/AKT pathway, controls chromosomal integrity and regulates the expression of the repair protein Rad51, reducing the incidence of spontaneous double strand breaks (Shen et al. 2007).

PTEN-deficient tumors exhibit genomic instability due to the down-regulation of Rad51 and the impaired homologous recombination, and result extremely sensitive to PARP inhibitors (Antonarakis and Armstrong 2011).

This sounds of even particular interest, if we consider that, during PC progression the impairment of DNA repair processes mediated by tumor hypoxia greatly contributes to the increase of the genetic instability of prostate cancer (Fan et al. 2004).

Hypoxia, in fact, occurs in 30–90 % of prostate tumors (Chan et al. 2007; Stewart et al. 2010).

Chronic hypoxia, down-regulates the expression and function of many of the DNA-dsb-associated genes, as RAD51 decreasing homologous recombination and DNA double-strand break repair (Vaupel and Mayer 2007).

Thus contributing to the overall genetic instability and aggressiveness of prostate cancer cells.

Tumor hypoxia is indeed progressively emerging as a common feature of prostate tumors associated with poor prognosis.

In-line with these findings, hypoxia-induced metastatic lesions are characterized by gene amplification, point mutation, hyper-mutagenesis and a large amount of DNA strand breaks (Tannock et al. 2005).

Thus, it is becoming increasingly clear that multiple approaches may be hypothesized to overcome radio-resistance of PC cells.

Targeting the hypoxic response has been shown to sensitize PC cells to ionizing radiation in vitro (Russell et al. 2003; Slupianek et al. 2001) and may be effective as a complement to radiotherapy of prostate cancer patients. The first attempts of RAD51 expression inhibition by imatinib mesylate (Gleevec) have provided encouraging results (Bristow et al. 2007).

As well, treatment with ABT-888 (Veliparib) has shown some efficacy in PTEN defective PC-3 prostate cancer cells (Barreto-Andrade et al. 2011; Mendes-Pereira et al. 2009).

In addition, ABT-888 enhanced the antitumor activity of TMZ in orthotopic human breast and prostate xenografts.

Radiosensitization in vivo has also been demonstrated using several PARPi: AG14361, GPI 15427, ABT-88 and E7016; all showed good radio-sensitization against colon, head and neck, lung and prostate cancer xenografts (Donawho et al. 2007; Calabrese et al. 2004a, b; Palma et al. 2009; Barreto-Andrade et al. 2011).

It could be then hypothesized that PARPi could be successfully used as monotherapy to achieve tumor control, and/or as radio-sensitizers of PTEN-deficient prostate tumors (Barreto-Andrade et al. 2011; Curtin 2012).

A further, extremely interesting, finding derives from a recent report indicating that PARPi can increase the vascular perfusion of tumors through direct vasoactive effects, thus increasing their oxygenation and radio-sensitivity (Liu et al. 2008), leading us to conclude that it may be possible that some PARP inhibitors could induce short-term, vasodilatory effects by virtue of their structural similarities to nicotinamide.

Nicotinamide, a weak PARPi, inhibits contraction of vascular smooth muscle, and its utility in combination with carbogen is being tested in radiotherapy clinical trials (Horsman 1995).

Recently, the AG14361 PARPi was shown to improve intra-tumoral perfusion and possibly reduce tumor hypoxia in mouse xenografts (Calabrese et al. 2004b). Additionally, pharmacological inhibition of PARP has been recently demonstrated to impair HIF-1a induction and angiogenesis (Martin-Oliva et al. 2006; Rajesh et al. 2006a, b).

ABT-888 has been shown to inhibit endothelial tubule formation as well as decreased tumor vascular density (Albert et al. 2007).

This could enhance tumor growth delay after radiotherapy by increasing tumor blood flow, enhancing drug penetration, and increasing oxygen concentrations to offset hypoxic cell radio-resistance. Vasoactive properties and/or anti-endothelial effects have also been documented for AG14361 and ABT888 (Albert et al. 2007; Calabrese et al. 2004a, b; Ali et al. 2009).

Accumulating clinical evidence indicates, in addition, that the short-term use of PARP inhibitors would be extremely well tolerated, even in patients who have undergone multiple previous cytotoxic therapies (Curtin 2012).

Several small-molecule PARP1 and PARP2 inhibitors are currently in preclinical and clinical trials, alone or in combination with DNA-damaging agents (Rodon et al. 2009; Rouleau et al. 2010).

The use of radio-sensitizers to target recognition and repair of DNA damage is becoming an emerging strategy to improve the efficacy of radiotherapy at lower IR doses (Ljungman 2009).

PARP is activated by ionizing radiation (IR) and chemotherapy agents, and this has provided the rationale to examine the combined effects of PARP inhibitors and genotoxic therapy in tumor models and in clinical trials (Donawho et al. 2007; Plummer et al. 2008; Powell et al. 2010).

Several aspects concerning the use of PARPi as radiosensitizers for PC are still to be better elucidated. Here we will briefly examine the most debated ones.

  1. 1.

    PARP inhibition has been shown to radiosensitize mainly replicating cells through the increase of unrepaired DSB (Noel et al. 2006; Dungey et al. 2008).

    This favors the increase of the therapeutic index of radiation therapy in highly replicating tumors (Kastan and Bartek 2004) as recently demonstrated in vivo, in colon, head and neck, lung and prostate cancer xenografts using several PARPi, as ABT-88, AG14361, E7016, GPI 15427 (Donawho et al. 2007; Calabrese et al. 2004a, b; Palma et al. 2009; Barreto-Andrade et al. 2011).

    However, the long-term success of radiation therapy of PC depends upon the eradication of mostly non-replicating tumor stem cells, that constitute up to 1 % of total tumor cells (Wong and Hill 1998).

    As it is well-known, cancer stem cells typically reside in hypoxic niches.

    Some PARPi, such as ABT-888, have shown the ability to radio-sensitize in vivo also hypoxic tumor clonogens.

    It seems, then, that at least some PARPi could improve the therapeutic ratio of clinical radiotherapy by overcoming both oxic and hypoxic radioresistance.

    These findings are still to be confirmed on large case–control studies. Nevertheless, they look very promising. Moreover, these PARPi would be used also as a complement for new biological imaging-guided hypoxic tumor regions-targeted, high doses-radiotherapy (“dose painting”) (Liu et al. 2008) and, some evidences, show that radiotherapy may induce prostate cancer cell death also through a terminal growth arrest (Schwarze et al. 2001). As indicated by the overexpression of markers of senescence, such as p21WAF1/Cip1 and p16INK4a (Stein et al. 1999), therapy-induced senescence is increasingly being reported as an alternative mode of cell death.

    It can result from several inducers, including accumulation of unrepaired DNA damage and is proposed to contribute to tumor control following treatment with cytotoxic agents (Roninson 2003; Lleonart et al. 2009). Some results in PC-3 cells and tumors have suggested that accelerated senescence may be a factor in the therapeutic response of some human tumors to IR combined with PARP inhibition (Efimova et al. 2010).

    A terminal growth arrest should probably be considered an adjunctive endpoint and novel therapeutic approach for radiotherapy of prostate carcinoma. PARP inhibitors are among the favorite candidates for inducing this purpose.

    However, this point still deserves consideration in clinical trials and, mainly due to the lack of reliable senescence-inducing agents, this area constitutes an open field for further research (Barreto-Andrade et al. 2011).

  2. 2.

    First generation PARP inhibitors have produced defects in lymphocytes and muscle cells differentiation in several cases. This side-effect may be due to the need of inhibit >90 % of PARP activity to produce a therapeutic impair of DNA repair (Satoh et al. 1994; Farzaneh et al. 1982; Johnstone and Williams 1982).

    However, the third generation of highly potent and specific PARP inhibitors has not produced these adverse effects, suggesting that they might have been only a result of an off-target effect specific for the first type of inhibitors.

    However, given the high potency of the new generation of PARPi, the systemic effects of near-complete PARP inhibition should be tested with additional studies on animal model (105. Konishi et al. 1986; Takahashi et al. 1984).

    As an example, PARP1 is required either for the protection of the cardiovascular system and for the development of memory (Pacher and Szabo 2007; Goldberg et al. 2009).

    As well, long-term PARP1 inhibition could also lead to secondary malignancies, particularly when inhibitors are administered with DNA damaging agents. This hypothesis is supported by several reports. Recently, a high incidence of cancers in mice knocked-out for Parp1 has been reported (Morrison et al. 1997; Tong et al. 2002, 2003).

    Reasonably, in each case the risk of occurrence of secondary tumors should be challenged against the chance of improving the therapeutic ratio of currently lethal cancers (Bristow et al. 2007).

    The better understanding of both acute and late effects of therapeutic DNA repair inhibition may allow oncologists to focus on the possible way to prevent second malignancies in PARPi-treated patients, by chemopreventive strategies or alternative pathway activation.

    Studies on large collections of tumor specimens will be essential to evaluate, in situ, new potential targets for complementary therapies (Antonarakis and Armstrong 2011).

    Lastly, it will be interesting to see how durable will be the response rates of patients treated with PARPi.

    It appears worrisome, in fact, that resistance to PARP inhibitors has been described in BRCA1- or BRCA2-deficient cancer cells, following to the reactivation of these genes by secondary mutations (Ashworth 2008; Sakai et al. 2008; Edwards et al. 2008).

  3. 3.

    Little is actually known about the effects of inhibiting PARPs other than PARP-1 and 2 (Rouleau et al. 2010).

    Among the 17 members of the ‘PARP superfamily’ identified to date, only PARP3, V-PARP and Tankyrase-1 and -2 (TNKS-1 and -2) have the ADP-ribose polymerizing activity (Hakame et al. 2008) PARP-3 co-operate with PARP-1 in the response to DNA double strand breaks (Boehler et al. 2011).

    Tankyrases (TNKS) 1 and 2 are involved in telomere maintenance (Midorikawa et al. 2006) and V-PARP is associated with large ribonuclear protein structures (cytoplasmic vaults), which are amplified in some drug resistance models (Cohen-Armon et al. 2004; Kickhoefer et al. 1999; Fang et al. 2006).

    A potentially specific tankyrase inhibitor, XAV-939, has been identified, raising the possibility that BRCA1- or BRCA2-mutant tumors might be successfully targeted without inhibiting PARP1 (Ju et al. 2004).

    To date, however, it is unclear to what extent the inhibition of other PARPs contributes to the cellular effects of PARP inhibitors. Only a few studies exist. Moreover, specific inhibitors of all the different PARP-family members are still incompletely available (Curtin 2005).

    This topic, in any case, will certainly be a matter of intense investigation in the near future.

At present, the prediction of radio-responsiveness of prostate cancer is based upon the pre-treatment PSA level/doubling time, Gleason score and T-stage (Nichol et al. 2005).

Novel therapeutic approaches, differentially targeting HR and/or NHEJ DNA-dsb repair, could necessitate of new identifiers of DNA repair (i.e., single nucleotide polymorphisms (SNPs), protein expression, functional assays for DNA damage sensing and repair) related to normal and tumor radio-sensitivity, to drive for individual prostate cancer therapy (Bristow et al. 2007).

These tests may result useful as biomarkers of the genetic instability, malignant progression and aggressiveness of tumor (Choudhury et al. 2006).

This approach may protect normal tissues, allowing the delivery of high doses of radiation and DNA repair inhibitors exclusively on tumor areas targeted by hypoxic signals from MRI, CT or PET-based imaging.

This is an exciting time for oncologists, radio-therapists and pathologist now able to surf over the mounting data concerning the molecular interactions responsible for DNA repair, to discover and apply new therapies based upon a direct collaboration between basic science, industry, academia, and regulatory agencies.

The chances to achieve a new integrative and interdisciplinary approach to prostate cancer patient care, based upon translational oncology, are indeed rapidly becoming reality.

We are now almost ready to take on the challenge to apply next-generation discovered biomarkers able to drive a successful control of previously untreatable, radio-resistant prostate cancers (Fig. 18.1).

Fig. 18.1
figure 1

“Synthetic lethality” in the therapy of PCa. Ionizing radiation kills eukaryotic cells through the induction of DNA- double-strand breaks (DNA-dsbs) that represent the most cytotoxic lesions. They are usually repaired through the homologous recombination (HR) and the non-homologous end joining (NHEJ) pathways that, in fact, result hyper-activated in normal cells in response to radiation-induced DNA damage. The non-repair of radiotherapy-induced DNA-dsbs causes genomic instability. The term “synthetic lethality” refers to a condition of simultaneous presence of mutation of two genes resulting in cell death. The most promising clinical translations of synthetic lethality concern cancers with specific defects in the HR-mediated repair of double-strand breaks that results in an extreme dependency of tumors on PARP1 action and BER to maintain genomic integrity. Basing on its fundamental role in DNA-repair, PARP-1 represents the ideal therapeutic target to kill cancer cells with loss of HRR function and to increase the efficacy of radio/chemotherapy. PARP inhibition leads to chromosomal instability, cell cycle arrest and apoptosis caused by the persistence of DNA lesions

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