Nanotechnology in Cancer Therapy: Targeting the ... - IngentaConnect

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Current Molecular Medicine 2010, 10, 626-639

Nanotechnology in Cancer Therapy: Targeting the Inhibition of Key DNA Repair Pathways K. Aziz1,2, S. Nowsheen3,4 and A.G. Georgakilas*,1,5 1

Department of Biology, Thomas Harriot College of Arts and Sciences, East Carolina University, Greenville, NC 27858, USA 2

Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA 3

Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA 4

Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA 5

Department of Physics, National Technical University of Athens, Zografou Campus, GR-15773 Athens, Greece Abstract: Cancer therapy has been changing over the decades as we move away from the administration of broad spectrum cytotoxic drugs and towards the use of therapy targeted for each tumor type. After the induction of DNA damage through chemotherapeutic agents, tumor cells can survive due to their proficient DNA repair pathways, some of which are dysregulated in cancer. Latest improvements in nanotechnology and drug discovery have led to the discovery of some very unique, highly specific and innovative drugs as inhibitors of various DNA repair pathways like base excision repair and double strand break repair. In this review we look at the efficacy and potency of these small chemical molecules to target the processing of DNA damage induced by standard therapeutic agents. Emphasis is given to those drugs currently under clinical trials. We also discuss the future directions of using this nanotechnology to increase the therapeutic ratio in cancer treatment.

Keywords: Cancer therapy, DNA damage, DNA repair, inhibitors, nanotechnology, base excision repair, double strand break repair.

INTRODUCTION All organisms are exposed on a daily basis to various genotoxic and deoxyribonucleic acid (DNA) damaging agents like ionizing radiations (-particles from radon decay, diagnostic X- and -rays, cosmic rays), non-ionizing radiations (UV), various chemicals and intracellular oxidative stress originating from various metabolic pathways leading to the production of free radicals like reactive oxygen and nitrogen species, ROS and RNS respectively [1-3] (Fig. 1). Primary cellular defense mechanisms against any free radicals consist of endogenous radical scavengers like glutathione (GSH) and antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) [4]. In addition, the cell will initiate a plethora of DNA repair mechanisms meant to correct any DNA damage eventually induced. DNA repair refers to the collective mechanisms by which a cell detects and corrects damage to its DNA content. The DNA repair efficiency of a cell is vital to the integrity of its genome, restoration of the original DNA structure and thus to the proper functioning and *Address correspondence to this author at the Biology Department, Howell Science Complex, East Carolina University, Greenville, NC 27858, USA; Tel: 252-328-5446; Fax: 252-328-4178; E-mail: [email protected] 1566-5240/10 $55.00+.00

homeostasis of the organism. Many genes that were initially shown to influence the lifespan of experimental models like mice have turned out to be involved in DNA damage repair and in general protection against oxidatively-induced DNA injury [5]. Experimental animals with genetic deficiencies in DNA repair often show decreased lifespan and increased cancer predisposition and incidence [6]. On the other hand, the unique ability of ionizing radiation or other radiomimetic drugs (like bleomycin and neocarzinostatin) [7, 8] to induce closely spaced i.e. complex DNA damage has been used as the basis for the therapeutic applications of these genotoxic agents towards the induction of enhanced cancer cell killing. Random energy deposition by ionizing radiation can induce a variety of DNA lesions ranging from single (SSBs) and double DNA strand breaks (DSBs), different types of oxidized bases with two of the most abundant 7,8-dihydro-8-oxo-2'-deoxyguanosine (8oxodG) and 5,6-dihydroxy-5,6-dihydrothymine (thymine glycol; Tg), apurinic-apyrimidinic (abasic, AP) sites and DNA-DNA or DNA-protein crosslinks [9-13] (Fig. 1). The most abundant lesions like SSBs and oxidized bases are expected to be primarily processed by base excision repair (BER) and to a lesser extent nucleotide excision repair (NER) [12, 14]. Quite surprisingly BER has been very recently implicated also in the © 2010 Bentham Science Publishers Ltd.

DNA Repair Inhibitors in Cancer Treatment

Current Molecular Medicine, 2010, Vol. 10, No. 7

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Fig. (1). Major DNA damage types and their repair pathways based on current status of knoweledge. The cells in every organism are getting exposed to various oxidizing, genotoxic and damaging agents ranging from exogenous environmental, medical, diagnostic sources like ionizing and non-ionizing radiations (X- or -rays, -particles, UV radiation), chemicals like benzo[a]pyrene and chemotherapy drugs to intracellular (endogenous) sources of oxidative stress. The final outcome is the production of reactive oxygen/nitrogen species (ROS, RNS), DNA lesions and adducts. The first frontier of cellular defense against DNA damage consists of endogenous radical scavengers like glutathione (GSH), antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) as well as sophisticated and highly specified DNA repair pathways. According to current status of knowledge, the major types of DNA damage and their repair are expected to be several DNA lesions like single strand breaks (SSBs) and oxidized bases like 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) and dihydroxy-5,6-dihydrothymine (thymine glycol; Tg) in a clustered or single (isolated) formation. All these lesions are expected to be processed by base excision repair (BER) while the involvement of nucleotide excision repair (NER) cannot be excluded. The formation of a double strand break (DSB) will lead to the activation of non-homologous end joining (NHEJ) or homologous recombination (HR) repair pathway. In the production of bulky lesions like DNA-protein or DNA-DNA crosslinks after exposure to UV radiation or platinum drugs the activation of NER, HR or photoreactivation pathways is expected. Recently, BER has also been implicated in the processing of crosslinks. In many cases, the cell will bypass DNA damage and enter DNA replication. Lesions that escape repair and enter replication are expected to be primarily repaired by mismatch repair (MMR) while the participation of additional repair mechanisms like global genome repair (GGR) or transcription-coupled repair (TCR) as subpathways of NER cannot be excluded depending on the efficiency of the major repair pathways to correct the damage or the location of the DNA lesions i.e. in actively transcribed DNA strands.

processing of some types of DNA crosslinks as reviewed in [15]. Ionizing radiation induces damage in DNA by direct ionization and through generation of free radicals that attack DNA and induce some or all of the above lesions (indirect effect). In addition to the prompt breaks induced by radiation some post-irradiation ones can be also formed as the result of the attempted repair of some sugar and base residues which can later be converted to SSBs or DSBs, a process often referred to as abortive excision repair [16]. Two or more DNA lesions of the same or different nature may be

produced in close proximity to each other on opposite DNA strands (double stranded lesions), generally within one-two helical turns of the DNA molecule. These various closely spaced bistranded types of DNA damage are called clustered DNA lesions and can include SSBs of varying complexity, oxidized base lesions (oxypurines and oxypyrimidines: oxybases), and regular as well as oxidized AP sites [17]. Even at doses as low as ~1 Gy (100 rad), ionizing radiation is capable of inducing all of the above types of DNA damage in the form of isolated lesions as well as in the

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form of clustered ones (1-10 bp apart) [18, 19]. It has been shown that clustered lesions constitute 50-80% of the total complex DNA damage [17, 20, 21]. As already described above, simultaneous processing of the lesions located on opposite strands may generate additional DSBs in addition to the ones directly (prompt or frank DSBs) induced by ionizing radiation and enhance cell death or genomic instability. Table 1.

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Mutagenic or lethal effects of ionizing radiation are thought to result principally from incomplete or incorrect repair of DNA lesions [14, 22]. While isolated damages are generally repaired quite efficiently, clustered DNA lesions have been suggested to be highly repairresistant or non-repairable and therefore considered as lesions of high biological significance [23, 24]. DNA clusters could be resistant to processing by

Genetic Disorders that Predispose Individuals to Cancer Via DNA Repair Pathway Defects

Syndrome

Mutation

Type of cancer

Repair pathway(s) affected

Incidence (USA) [127]

Source(s)

Ataxia Telangiectasia

ATM

Lymphoma, breast, brain, stomach, bladder, pancreas, lung, ovaries, T cell prolymphocytic leukemia, B cell chronic lymphocytic leukemia, sporadic colon cancer

DSB repair

1 in 40,000 (breast), less than 1% in others

[128-131]

Nijmegen Breakage

NBS1 gene (MRN complex)

Lymphoma

HR

less than 200,000 people in the US

[131-137]

Lynch

MMR genes (MLH1, MSH2, MSH6, PMS2)

Colorectal cancer, cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, prostate, cancer of the endometrium and ovaries

MMR

between 1:2000 and 1:660

[138-143]

Li-Fraumeni

CHK2 and p53

Osteosarcoma

MMR

Very rare (only 400 people in 64 families)

[144-149]

Werner

WRN, Rad 51

Osteosarcoma, colon, rectal, lung, stomach, prostate, breast, thyroid, soft tissue sarcomas

NHEJ, HR

1 in 200,000 (osteosarcoma),

[150-154]

1 in 20,000 Xeroderma Pigmentosum

XPD

Skin cancer

NER

1:1,000,000

[155-161]

Bloom

BLM

Leukemia, lymphoma, melanoma, bladder cancer

HR

1 per 48,000 people of Ashkenazi Jewish descent, less than 1:200,000 in others

[152, 162168]

Baller Gerold

RECQL4

Osteosarcoma

HR, BER

1:1,000,000

[151, 169]

Rapadilino

RECQL4

Osteosarcoma and cutaneous cancers

HR, BER

1:1,000,000

[151, 169]

Cockayne

CSA, CSB

NOT linked to cancer

NER

1 in 100,000

[170-178]

XPD, XPB

NOT directly linked to cancer

NER

1:200,000

[179]

Fanconi Anemia

FANC

Acute myeloid leukemia (AML), head and neck, gynecological, and/or gastrointestinal squamous cell carcinomas

DNA crosslink repair

1-5 in 1 million

[166, 180187]

DNA LIG4 deficiency

LIG4

Pancreatic, lung

NHEJ

1:200,000

[188-191]

XCIND

Rag1 and Rag2

Lymphoma

NHEJ

1:200,000

[192]

RS-SCID

Artemis

Lymphoma

NHEJ

Navajo 1 in 2000

[189]

Rothmund Thompson

RECQL4

Osteosarcoma

BER

Less than 1:200,000

[41, 169]

Cernunnos Deficiency (XLF)

XLF

Lymphoma

NHEJ

Less than 1:200,000

[129]

ATR-Seckel

ATR

Leukemia

DSB repair

Less than 1:200,000

[189, 193]

Trichothiodystrophy


glycosylases or endonucleases, as shown for synthetic oligonucleotides containing clusters of specific composition and configuration [25-30]. Such repairresistant clusters could persist for a substantial time after irradiation as suggested by experimental and theoretical studies [31, 32]. The idea about the existence of clustered DNA damage was initially introduced by Ward as locally multiple damaged sites (LMDS), i.e., several closely spaced damages within a short DNA segment that could be produced by ionizing radiation [33, 34]. Ward introduced the idea of clustered DNA lesions in order to give an explanation for the increased lethality associated with exposure of cells to relatively low doses of ionizing radiation. Since then, quite a few studies have been performed in this area but very few focus directly on the repair of these lesions by a human cell which is expected to be primarily performed by the BER pathway, if repaired at all [24, 31, 35].

DNA REPAIR DEFICIENCIES The lower fidelity or deficiencies of repair mechanisms responsible for removing or bypassing DNA damage and restoring the original sequence after exposure to intracellular or extracellular damaging agents such as ROS, estrogen metabolites, ionizing radiation, cigarette smoke, and environmental or therapeutic chemicals is considered as one of the most well-accepted etiological hypotheses in the promotion of mutagenesis and carcinogenesis [36]. Numerous studies suggest the important role of oxidativelyinduced DNA damage and its repair in cancer, aging and, in general, in human pathogenesis [3, 14, 37, 38] (Table 1). Exposure to radiotherapy-relevant doses of ionizing radiation or some chemotherapeutic drugs like bleomycin and neocarzinostatin will induce a variety of complex DNA damage consisting of DSBs and nonDSB clustered DNA lesions as described above and in Fig. (1). The majority of clinically used drug inhibitors or the ones under development, target pathways relating to the processing of these complex lesions like BER, NER and DSB repair pathways like non-homologous end joining (NHEJ) or homologous recombination (HR). Of course in many cases the cell will ‘choose’ to bypass the damage using various specialized polymerases like the polymerase , , μ, or Y-family [39, 40] and enter replication. In this scenario, other repair pathways like the mismatch repair pathway (MMR) will kick in and attempt to repair the damage [1]. This ‘bypass’ strategy of the DNA repair systems will usually result in high mutation rate. Abnormalities in DNA repair pathway components give rise to several genetically inherited syndromes (Table 1). Predisposition to cancer is highly elevated in many of these syndromes, highlighting the importance of fully functional DNA repair pathways in maintaining the integrity of our genome. As discussed earlier, all major repair pathways are linked to specific types of damages, e.g. BER and NER are the principal pathways responsible for combating


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simple oxidative DNA damages like 8-oxodG, Tg, and 2-deoxyribonolactone [41, 42]. However the generation of a DSB is one of the several possible outcomes that may result from an attempt to simultaneously repair clustered DNA lesions that are in close proximity on opposing strands [43-45]. Stalled replication forks during DNA replication at these junctions may also give rise to a similar scenario, where the single strand break (SSB) degenerates to form a DSB [46]. This portrays the close relationship between DNA repair pathways which are originally responsible for repair of distinct types of DNA damages. The philosophy behind effective targeted cancer therapy involves induction of DNA damage in tumor cells as selectively as possible, while minimizing concurrent damage in normal cells, and subsequently taking advantage of possible DNA repair pathway defects in these tumor cells to abrogate the repair and selectively kill them. A classic example is borne by the therapies designed around poly ADP ribose polymerase (PARP) inhibitors and breast cancer susceptibility proteins 1/2 (BRCA1/2) germ-line deficiency in many cancer patients (Table 2). The primary pathway responsible for correcting a certain type of error(s) may be inhibited using chemotherapeutic agents if we definitely know that normal cells have the ability to use a second independent repair pathway to survive. In addition, we assume that this specific repair pathway(s) is compromised in the tumor cells due to mutations; hence, causing the tumor cells to undergo apoptosis. Recent advances in nanotechnology and drug discovery have identified several promising inhibitors against key proteins in the DNA repair pathways (Table 2). Many of these inhibitors are small molecules that share structural similarities with cofactors required for enzymatic functions of these protein moieties. The available anti-cancer drugs have distinct mechanisms of action. Some induce DNA damage in the cancer cell. Others might inhibit DNA synthesis or mitosis, thus preventing cell replication and division. Drugs like methotrexate and hydroxyurea stop the synthesis of DNA molecule by disrupting nucleotide synthesis [47, 48]. Others like cisplatin directly damage the DNA in the nucleus, disrupting replication [49]. Drugs like Taxol break down the mitotic spindle, preventing DNA synthesis [50]. Irrespective of the mechanism of action, the result is the halt of cellular replication.

TARGETING BASE EXCISION REPAIR (BER) PROTEINS Base excision repair is principally responsible for repair of SSBs and base lesions caused by oxidation, alkylation, and deamination. BER can proceed via two pathways, short patch (SP) repair and long patch (LP) repair, depending on whether the damage is direct or indirect via radiolytic attack in the DNA [51]. Base damages are examples of damage mostly but not exclusively induced indirectly by free radical attack (ROS, RNS) while direct ionizations by radiations like

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Table 2.

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Clinical Trials Targeting DNA Repair Mechanisms that are Currently in Progress

Type of cancer

Pathway

Proteins targeted

Drug

Institution

Trial

Additional information

Source

Malignant glioma

BER

PARP 1

BSI-201 and Temozolomide

Bipar sciences

Phase I/ II

The purpose of this study is to determine the maximum tolerated dose (MTD) of BSI-201 when administered as an IV infusion in combination with temozolomide (TMZ) after the completion of standard radiation therapy and concomitant TMZ.

[194]

Urothelial carcinoma

MMR, NER

Rad9, Hus1, Rad1, ATR, Chk1

Cetuximab (Erbitux), Cisplatin, Gemcitabine

University of Michigan

Phase II

This study compares the overall response rate of combination treatment of gemcitabine and cisplatin, given with or without cetuximab.

[194]

Metastatic breast cancer

BER

PARP

ABT-888 and Temozolomide

Massachusetts General Hospital

Phase II

This study aims to find if the combination of ABT-888 and temozolomide is a safe and effective treatment.

[194]

Solid tumors, leukemia, lymphoma

BER

PARP

ABT 888

Warren Grant Magnuson Clinical Center

Phase I

This trial is studying the side effects and best dose of ABT-888 when given together with cyclophosphamide in treating patients who did not respond to previous therapy.

[194]

ACE

Captopril

Robert H. Lurie Cancer Center

Phase II

This randomized trial is studying how well captopril works in decreasing side effects and improving the quality of life in patients who have received radiation therapy with or without chemotherapy.

[194]

Lung cancer

Breast cancer or ovarian epithelial cancer

BER

PARP

AZD2281 and Carboplatin

Warren Grant Magnuson Clinical Center

Phase I

Effect of the combination treatment of PARP Inhibitor AZD2281 (KU-0059436) and Carboplatin in cancer treatment.

[194]

Brain tumors

NHEJ

DNA PKcs

Lithium

Vanderbilt University

Phase I

Lithium protects normal hippocampal neurons from radiation induced apoptosis, but not cancer cells

[119, 194]

Bowel cancer

BER

PARP

Olaparib

AstraZeneca

Phase II

This study assesses the efficiency and safety of the PARP inhibitor, Olaparib, in previously-treated patients with Stage IV, measurable colorectal cancer, which is graded by MSI status.

[194]

DNA repair 6 protein O alkylguanine alkyltransferase

Decitabine and Temozolomide

U Pittsburgh

Phase I/II

Combination effect of Decitabine and Temozolomide

[194]

To find the optimum dose for TRC102 when used in combination with Pemetrexed in patients without curative therapy.

[194]

Melanoma

Metastatic solid cancer

BER

APE 1

TRC102 and pemetrexed

Tracon Pharmaceuticals Inc.

Head and neck squamous cell carcinoma and melanoma

HR

NBS1, P53

Dbait

Institut Curie

NA

To sensitize tumors to radiotherapy using small molecules that mimic DNA damage.

[105]

Colorectal cancer

MMR

Topoisomerase I

Irinotecan

France

Phase III

To assess the effectiveness of the drug with or without chemotherapy in patients with stage III colon cancer.

[194, 195]

X-rays, -particles serve as an example of direct damage (like SSBs, DSBs). At first, the damaged base is removed by a damage-specific DNA glycosylase.

This creates an apurinic or apyrimidinic (AP) site. Consecutively AP endonuclease1 (APE1) cleaves 5 to the sugar missing the base, generating a SSB. Short


patch repair in case of single nucleotide damages [52] involve recruitment of PARP-1 or PARP-2 followed by recruitment of the scaffold protein XRCC1. DNA polymerase (Pol ) is the next player responsible for replacement of the damaged nucleotide. For restoration of the intact DNA, DNA ligase III (Lig III) is recruited to seal the nick [14]. On the other hand, for LP repair, in case of repair of at least two nucleotides [53], PARP-1 is recruited followed by XRCC1. The scaffold protein brings in polynucleotide kinase (PNK) to convert the damaged ends to 5-phosphate and 3hydroxyl moieties, enabling proliferating cell nuclear region (PCNA) and DNA polymerase / extend to fill the gap by 2-15 nucleotides and then flap endonuclease 1 (FEN1) cleaves the resulting flap. The nick in LP repair is ligated by DNA ligase I (Lig I). Pol is thought to be involved in the initiation of strand displacement of LP pathway, but even Pol deficient extracts of mouse embryonic fibroblasts showed active LP repair [54, 55]. Therefore, alternative polymerases may also be able to carry out this DNA synthesis. The circumstances that favor a specific BER route are not clear. Some evidence suggests it could be dependent on the cell cycle phase [56] or intracellular adenosine triphosphate (ATP) levels [57]. Lower levels of ATP around the AP site are likely to promote LP repair as opposed to SP BER repair. Cells in S/G2 phase seem to be taking LP repair route while SP repair is seen all throughout interphase. Lig III and XRCC1 are the two important components that regulate the switch between LP and SP repair. Under conditions of adequate ATP, ligation by Lig III prevents strand displacement leading to SP repair. In case of ATP shortage, XRCC1 can stimulate Pol strand displacement and LP repair. It has also been shown via site directed mutagenesis studies designed against the active site of Lig III, that LP repair is indeed dependent upon the ligation activity of this enzyme [58]. PARP-1, the most focused-on member of the PARP family, is the most important BER component in the light of cancer therapy. It is vital for DNA repair and cell survival [51, 59]. When activated by events like DNA repair, recombination, replication, DNA binding drugs, or oxidative stress, PARP-1 functions by cleaving nicotinamide adenine dinucleotide cation (NAD+) into nicotinamide and ADP-ribose and covalently binds the ADP-ribose to acceptor proteins. Automodification of PARP by poly ADP-ribosylation results in its inhibition [60]. One of the important functions of PARP in promoting BER is its ability to perform ADP-ribosylation of histone proteins allowing decondensation of the chromosome [61-66]. PARP-1 is composed of three domains of which one is referred to as the DNA binding domain containing two zinc finger domains. This also contains a DNA nick sensor and nuclear localization signal (NLS) within the caspase cleavage site. The other two domains are the automodification domain and the NAD-binding region containing the catalytic sites [67]. In terms of location, inactive PARP-1 resides primarily in the nucleoplasm, while some is also found in the mitochondria [68]. In reponse to DNA damage it


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gets recruited to sites of strand breaks. Severe DNA damage could overactivate PARP causing massive synthesis of Poly ADP-ribose, hence depleting NAD+ and ATP and therefore promoting mitochondrial dysfunction or necrotic cell death [49]. Necrosis is not a desired method of cell death even for tumor cells since disintegration of the plasma membrane can cause leakage of cell contents into surrounding tissues. PARP-1 promotes DNA repair in response to genotoxic stress [69]. It can be hypothesized that over-activation of PARP-1 in tumor cells promote necrosis and subsequently increased oxidative stress (indirect) around the perimeter of the tumor, eventually leading to damage in surrounding tissues, an effect perhaps mediated by ROS. PARP-1 may also increase oxidative stress by regulating expression of inducible nitric oxide synthase (iNOS), an inflammatory mediator at the transcriptional level [70-73]. Therapeutic studies designed around PARP inhibitors have burgeoned in the last seven years. Majority of these studies use PARP inhibitors for enhancement of the cytotoxic effects of DNA damaging chemotherapeutic agents like topoisomerase I inhibitors and methylating agents along with radiosensitization. Some in vitro and in vivo studies are also focusing on its use as a single agent for killing cancer cells deficient in DNA repair. The early inhibitors like 3-aminobenzamide lacked specificity and potency. Currently a number of promising clinical trials are also being carried out on PARP inhibitors (Table 2). A phase II research study from Massachusetts General Hospital, is trying to find out if the combination of ABT888 and temozolomide is safe and effective in treating patients with metastatic breast cancer (Table 2). PARP is responsible for repairing cancer cells damaged by radiation therapy. ABT-888 is a PARP inhibitor that prevents cancer cells from repairing themselves and as a result they die. The other drug in this study is temozolomide, a drug designed to damage DNA in order to prevent cancer cells from reproducing. The ability of chemotherapeutic drugs like temozolomide to kill cancer cells is enhanced by PARP inhibitors like ABT-888 as it prevents cancer cells from repairing their DNA. The combination of ABT-888 and temozolomide has been used in a clinical trial for treatment of different cancers and current information for this research study suggests that the combination may help to inhibit growth in breast cancer. A similar study has been focusing on the effect of BSI-201 and temozolomide. BSI-201 is an intravenous PARP inhibitor for which no normal tissue toxicity has been reported so far [74, 75]. Since myelosuppression and normal tissue toxicity have been emerging as dose limiting problems with PARP inhibitors [76], the BSI-201 study bears promise. The effect of combined therapy of ABT-888, a PARP inhibitor, with cyclophosphamide, a DNA alkylating agent, in patients bearing solid tumors or lymphoma is also being studied at the Warren Grant Magnuson Clinical Center (Table 2). The same institution leads another ongoing Phase I trial for the PARP inhibitor AZD2281 combined with carboplatin in BRCA1/2

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mutation carriers with breast or ovarian cancer and triple negative breast or ovarian cancer. Triple negative breast cancers are described to be estrogen, progesterone receptor and human epidermal growth factor receptor 2 (HER2) negative [77]. This scenario has gained particular attraction in the last few years since these mutant cells are very sensitive to PARP inhibitors. Rottenberg et al. have tested the efficacy of AZD2281 in inhibition of growth of BRCA1 deficient mammary tumors in vivo. In xenograft models, significant tumor regression was observed upon AZD2281 treatment. Mechanistic insights to AZD2281 resistance was explored to find out that expression of the efflux transporters Abcb1a and Abcb1b which encode the murine P-glycoproteins (P-gp) were drastically increased in the AZD2281 resistant tumors. The finding was strengthened by blocking the drug transport activity using a P-gp inhibitor, tariquidar, which restored the potency. Combination treatment of AZD2281 with cisplatin or carboplatin significantly prolonged recurrence free and total survival time [78]. In another study, chromosome analysis in embryonic stem cells lacking wild type BRCA1 or BRCA2 showed frequent major aberrations upon treatment with KU005868, a small molecule inhibitor of PARP. The damage was not confined only to chromatid breaks but complex chromatid aberrations such as triradial and quadric-radial chromosomes were also examined. These are indicative of failure to carry out HR repair [79]. Knowing that PARP is required for the efficient repair of DNA SSBs during BER and that PARP inhibition leads to persistent single strand gaps in DNA, Farmer et al. proposed a model explaining the sensitivity of BRCA1/2 mutant cells to PARP inhibitors. If the earlier-mentioned single strand gaps are encountered by a replication fork, arrest would occur and the single strand gaps may degenerate into DSBs. In a normal cell, RAD51 dependent HR, a process involving both BRCA1 and BRCA2, would efficiently repair the DSB. In the absence of BRCA1 and BRCA2 persistent chromatid breaks are formed since the replication forks cannot be restarted and therefore collapses [79]. Loss of two DNA repair pathways leads to synthetic lethality [80]. Alternative error prone DSB repair mechanisms, like NHEJ would cause large numbers of chromatid breaks and aberrations, leading to loss of viability. Several other HR components like RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA and FANCC were also reported to display sensitivity to PARP inhibitors [67, 81]. In addition, a clinical trial designed against the BER protein APE1 is studying the optimum dose for TRC102 when used in combination with pemetrexed in patients without curative therapy (Table 2). PARP-1 has been the prime target for cancer therapy in the BER pathway, therefore using nanotechnology as our tool and designing small

Aziz et al.

molecules that target other proteins in this pathway, cancer treatment can advance further.

TARGETING DSB REPAIR PROTEINS The two principal processes for repair of DSBs are the error free process of HR and the error prone NHEJ [82]. NHEJ is thought to be prevalent when a homologous template is not available for HR. It has been shown that NHEJ is independent of the cell cycle phase, whereas HR is though to be prevalent during late S and G2 phases [83, 84]. Other factors may also determine the use of a certain DSB repair pathway. NHEJ begins with Ku70/80 heterodimer binding to the DNA ends at the damage site. The Ku complex binds to both open ends and summons the DNAdependent protein kinase, catalytic subunit, also known as DNA-PKcs. DNA-PKcs has the capability to undergo autophosphorylation [85, 86] leading to processing of the damaged ends followed by ligation. The ligation is carried out by ligase IV/XRCC4 complex. The XLF/Cernunnos protein interacts with XRCC4 and stimulates this reaction [87]. Patients with the genetic Cernunnos deficiency are predisposed to lymphoma and patients with LIG4 deficiency are predisposed to pancreatic and lung cancer (Table 1). Compatibility of the DNA ends that are to be joined is an important factor for DNA PKcs autophosphorylation and ligation. Hence in cases of damages stretching for several base pairs, DNA polymerases and other nucleases may participate in NHEJ prior to ligation. The dynamics of NHEJ complex formation and dissociation before complete repair of DSB together with the processing step by polymerases and nucleases increase susceptibility to deletions and translocation making the process prone to error [88]. Besides repairing DSBs generated by endogenous and/or exogenous source, NHEJ also participates in repair of DSBs formed during T and B cell differentiation by V(D)J recombination [89]. Variable (V), diversity (D) and joining (J) regions come together during synthesis of mature V(D)J exons in B and T cells. RAG1 and RAG2 create DSBs at the junction between conserved recombination signal sequences (RSSs) and coding DNA segments. The intervening sequence is excised and coding sequences need to be ligated. Blunt ends are created at the RSS while the coding ends bear a hairpin structure linking the top strand to the bottom strand. This is where NHEJ participates for the repair of the DSB [90]. The coding end DNA hairpin structures are opened by a protein termed Artemis. The genetic syndromes RSSCID and XCIND are deficient in Artemis and RAG1/2 respectively, predisposing individuals to lymphoma (Table 1). Homologous recombination is the preferred method of DSB repair when a homologous template is available. Once a DSB is detected, it gets processed by nucleolytic cleavage to generate single strand tails with 3-OH ends. The major players in this activity are the Mre11 complex proteins [91] that include Mre11, Rad50 and Nbs1 (MRN complex), although CtIP, a


single strand specific endonuclease, is associated with the complex [92, 93]. PIKK family members, ATR and ATM, are activated by the MRN complex to regulate cell cycle progression and allow time for DNA repair [94, 95]. BRCA1, which bears an ubiquitin ligase activity, is responsible for physically interacting with CtIP and polyubiquitinating it. PCNA binding is also important for recruitment of CtIP to the site of the damage [96]. Replication Protein A (RPA) forms a recombinase filament on the single stranded DNA ends preventing formation of secondary structures. The BRCA1 complex recruits BRCA2 via PALB2. BRCA2 catalyzes the nucleation of RAD51 on to the free 5 end of the double stranded DNA-single stranded DNA junction. A D-loop intermediate is created by invasion into a homologous sequence and DNA polymerase extends the chain from the 3’ end of the invading strand and captures the second DNA end by annealing to the extended D loop. The two structures formed are described as Holliday junctions and gets resolved to generate the products. RAD52 and RAD54 interact with RAD51, with RAD52 mediating the recombination and participating in ssDNA binding and annealing; while RAD54 stimulates the D loop reaction, aids in translocase activity and induces superhelical stress in dsDNA [97-99]. The process may also proceed via different mechanisms that do not introduce crossing over possibilities [100-102]. Several helicases have been shown to be involved in the resection activity, including BLM, WRN and RECQ proteins. Mutations in these predispose patients to different types of cancer including osteosarcoma (Table 1). Previous studies from our group and other groups have shown an actual involvement of BRCA1 in the processing of non-DSB oxidatively induced single and clustered DNA lesions suggesting a potential additional role of this key DSBrepair protein in other independent pathways like BER [24, 103, 104]. Radioresistance is a commonly observed phenomenon in cancer patients. The enhanced repair of radiation induced DNA damage in cancerous cells seems to associate with the observed ‘resistant phenotype’ of these cells. Therapeutic strategies are being designed to overcome this limitation. In a recent study, Quanz et al. have shown how mimicking DNA damage using nanotechnology can trigger recruitment of the repair proteins and disorganization of DNA damage signaling hence increasing radiosensitivity of the tumor cells. The drug called Dbait that mimics DSBs was tested out in vitro and in vivo showing promising results. Dbait has been shown to activate DNA PK and increase levels of -H2AX, a well characterized in-situ marker of DNA DSBs [14]. In xenograft models of squamous cell carcinoma and melanoma, Dbait was seen to induce regression of the tumor when used in conjunction with radiation therapy [105, 106]. Glioblastoma is a common malignant brain tumor that is difficult to treat. The average survival after diagnosis has failed to exceed one year with current treatments [107]. Westhoff et al. have used the


633

pyridinylfuranopyrimidine inhibitor PI-103, to chemosensitize glioblastoma cells for apoptosis by inhibition of DNA repair. PI-103 targets the PI3K/Akt pathway, which has been closely linked with DNA PK activation [108]. Using doxorubicin to induce DNA damage, the amount of -H2AX foci formation in response to treatment of PI-103 and the DNA-PK inhibitor NU7026 were not significantly different. In addition, combined treatment by both inhibitors did not lead to a further increase in -H2AX levels. This suggests that PI-103 is essentially leading to DNA PK inhibition [109]. Our group has recently shown that DNA-PK inhibition using the highly specific inhibitors IC86621 and NU7026 leads to the accumulation of oxidative DNA lesions traditionally repaired by BER or NER, suggesting possible involvement of DNA-PK also in these repair pathways [110-112]. Cranial irradiation, the primary treatment modality for brain cancers, causes neurological deficiencies like memory loss and intellectual impairment [113-118]. Yang et al. have shown that lithium prophylaxis can combat this problem. Lithium, an inhibitor of glycogen synthase kinase–3 (GSK3), has been shown to protect normal tissues and not cancer from radiation induced apoptosis, accelerating the repair of DSBs in normal tissues through enhanced NHEJ [119]. Thus the use of this small molecule can be used as a selective tool while treating primary and metastatic brain cancers. An alternative potential target for cancer therapy is the epidermal growth factor receptor (EGFR), which is expressed at high levels in several cancers [120]. The PI3K and NHEJ pathway are closely linked downstream targets of EGFR pathway. Friedmann et al. have tested the combination treatment of EGFR tyrosine kinase activity inhibitor gefitinib along with cisplatin in a breast cancer model using MCF-7 cells. Treatment with gefitinib blocked the increase in EGFR phosphorylation observed with cisplatin treatment alone. Interestingly, the levels of DNA-PKcs were reduced. Co-immunoprecipitation of EGFR and DNAPKcs showed increased interaction upon gefitinib treatment, the functional relevance of which was not clear. Using a PI3K inhibitor LY294002, the inhibition of cell proliferation and DNA repair was seen to be identical to Gefitinib treatment suggesting similar mechanisms of action [121]. Erlotinib, another tyrosine kinase inhibitor, can be used to sensitize cancer cells to DNA damage. Erlotinib is being used to treat non-small cell lung cancer and pancreatic cancer among others. Similar to gefitinib, erlotinib functions by targeting the EGFR tyrosine kinase. This pathway is often dysregulated in different forms of cancer. The inhibitor binds to the ATP binding site of the EGFR, preventing the required autophosphorylation required for signal transduction [122]. Overall, it is evident that currently, several well characterized DNA repair pathways involving a plethora of associated DNA repair proteins exist,

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promising exciting prospects as potential targets for selective and efficient cancer therapy.

2009/2010 ECU Research/Creative Activity Award and the Biology Department, East Carolina University.

CONCLUSION

ABBREVIATIONS

Targeted therapies are also being designed against DNA repair pathways other than the ones mentioned. A clinical trial designed around MMR and NER proteins is exploring the effects of combined treatment of gemcitabine, a nucleoside analog and cisplatin, a DNA cross linking reagent, given with or without the EGFR inhibitor cetuximab in urothelial carcinoma patients (Table 2).

HR

= homologous recombination

NHEJ

= non-homologous end joining

NBS1

= Nijmegen Breakage Syndrome 1

MMR

= mismatch repair

BER

= base excision repair

NER

= nucleotide excision repair

Ineffective or non-specific treatments consume a large portion of patient care expenditures. Researchers are starting to think about the amount of funding being injected towards drug discovery and that patient treatment would be utilized more efficiently if their use was targeted according to the particular patient’s mutation profile, after genome sequencing. For example, if a BRCA1 mutation has been diagnosed in a breast cancer patient, only therapeutic strategies effective against that particular subgroup of the BRCA1-deficient cancer cells could be implemented [123]. Dissecting these subsets of cancer cells and tumors according to gene and pathway defects are therefore important for targeted cancer therapy. Moreover because of age, sex, diet and organ function differences between patients, drug metabolism is not uniform. The problem is increased when there is a mutation in the gene encoding a drug metabolizing enzyme, transporter, or target molecule, perhaps a polymorphism. This may affect their expression, activity or affinity to drugs therefore influencing the drug’s pharmacokinetics and pharmacodynamics [124]. Platinum based DNA damaging compounds cause damages that are generally repaired by NER and BER. However patients bearing a polymorphism of the XPD gene or XRCC1 genes, involved in NER and BER respectively, have poor response to oxaliplatin therapy [125, 126].

PARP

= poly ADP ribose polymerase

DNA

= deoxyribonucleic acid

ROS

= reactive oxygen species

RNS

= reactive nitrogen species

UV

= ultraviolet

GSH

= glutathione

SOD

= superoxide dismutase

CAT

= catalase

GPx

= glutathione peroxidase

SSB

= single strand break

DSB

= double strand break

Tg

= thymine glycol

It is evident that targeted cancer therapy using nanotechnology to target DNA repair pathways bears promise. We can effectively target DNA repair pathways to increase the therapeutic ratio for cancer treatment, selectively killing cancer cells. We need to address though potential long-term toxicity or resistance issues due to the use of these drugs while identifying new targets. A thorough understanding of DNA repair pathways dysregulated during carcinogenesis and neoplastic progression, as well as types of DNA damage induced during cancer development, may hold the key to the breakthrough in improving therapy in the fight against cancer.

ACKNOWLEDGEMENTS We apologize to investigators whose work could not be cited due to space limitations. This work was supported by funds provided to Dr. Georgakilas by a

8-oxodG = 7,8-dihydro-8-oxo-2'-deoxyguanosine AP

= apurinic-apyrimidinic

LMDS

= locally multiple damaged sites

LP

= long patch

SP

= short patch

APE1

= apurinic-apyrimidinic endonuclease 1

Pol B

= DNA polymerase

PCNA

= proliferating cell nuclear region

FEN1

= flap endonuclease 1

PNK

= polynucleotide kinase

ATP

= adenosine tri phosphate

NLS

= nuclear localization signal

Lig

= DNA ligase

RSS

= recombination signal sequence

XCIND

= Xray sensitivity, Cancer, Immunodeficiency, Neurological aberrations, and Double stranded DNA breaks

RAG

= recombination-activating proteins

NAD

= nicotinamide adenine dinucleotide

iNOS

= inducible nitric oxide synthase



BRCA 1 = breast cancer 1, early onset susceptibility protein BRCA 2 = Breast Cancer protein

Type

2

[4] [5]

susceptibility

HER 2

= human epidermal growth factor receptor 2

[6]

RPA

= replication protein A

[7]

ATR

= Ataxia telangiectasia and Rad3 related protein

ATM

= Ataxia telangiectasia mutated

CHK

= checkpoint homolog

FANCD

= Fanconi anemia complementation group D

[8]

[9]

FANCA

= Fanconi anemia complementation group A

[10]

FANCC

= Fanconi anemia complementation group C

[11]

CtIP

= C-terminal Binding Protein Interacting Protein

[12]

MRE

= meiotic recombination protein

RECQ

= ATP-Dependent DNA Helicase Q4

DNA PK = DNA-dependent protein kinase

[14]

-H2AX

= gamma histone 2A

PI3K

= Phosphoinositide 3-kinase

AKT

= protein kinase B

GSK

= glycogen synthase kinase

EGFR

= epidermal growth factor receptor

XPD

= xeroderma pigmentosum group D

PMS

= post meiotic protein

WRN

= Werner syndrome RecQ helicase-like, Werner syndrome protein

BLM

= blooms syndrome protein

CSA

= cockayne syndrome group A protein

CSB

= cockayne syndrome group B protein

ACE

= angiotensin converting enzyme

GGR

= global genome repair

TCR

= transcription coupled repair

segregation

[13]

[15]

[16]

increased

[17]

[18]

[19]

[20]

[21]

[22] [23]

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Received: April 20, 2010

Revised: June 09, 2010

Accepted: June 10, 2010

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