Treating prostate cancer with PARP1 inhibitors

Recently, the augmented immunodetection of PARP-1 was associated with prostate cancer progression and prediction of biochemical recurrence [138]. Preclinical data also indicated that PARP inhibitors might sensitize cancer cells and potentiate the effects of radiotherapy and chemotherapy. Interesting, inhibition or depletion of PARP-1 by antisense RNA [139], chemical inhibitors [140-142], or by the expression of dominant negative mutants (4-5), promotes genomic instability [143], as revealed by increased DNA strand breakage, gene amplification, micronuclei formation, and sister chromatide exchanges (SCE) in cells exposed to genotoxic agents. Marked SCE frequency has been observed in PARP-1 deficient cell lines and treated with different inhibitors against PARP-1 activity [144]. Depletion of PARP-1 was indicated as the main contribution to genomic alterations that may promote aberrant expression of cell proliferative genes, which may initiate cancer formation or progression. These observations implicate PARP-1 as a guardian of the genome, facilitating DNA repair and protection against DNA recombination by DNA lesion recognition [144] Accordingly, nuclear PARP-1 protein overexpression was associated with poor overall survival in early breast cancer [145]. PARP inhibitors have also been implicated in the modulation of the mechanisms driving apoptotic cell death [146]. Therefore, evidence correlating increased PARP-1 activity with tumor progression has opened a new avenue for the utilization of PARP inhibitors, which may impair the DNA repair machine. These effects may increase sensitivity of prostate tumor cells to DNA damaging agents by improving the efficiency of cancer therapeutics.

An early innovative therapy to treat prostate cancer cells was to enforce the binding of DNA strand breaks to a dominant-negative mutant of the DNA-binding domain of PARP. The recombinant plasmid inhibited the function of PARP-1 and sensitized prostate tumor cells to the lethal effects of ionizing radiation or etoposide (VP-16), with a markedly reduction of cell survival and induction of apoptosis [12]. The pharmacological inhibition of PARP-1 by benzamide pharmacaphores mimics the nicotinamide moiety of NAD+, occupying the donor site [147]. For example, the 3-aminobenzamide (3-AB) was shown to inhibit DNA excision repair and radiosensitize cells to ionizing radiation through impaired DNA repair [148, 149]. 3-AB is also know to inhibit the family of mono(ADP-ribose) transferases, which can produce non-specific effects independent of PARP-1 inhibition (Milam, 1984). Therefore, more potent and highly specific PARP inhibitors that promote oxid radiation sensitizer enhancement ratios have been developed. These new specific compounds (Table 4) are dependent of the cell line and inhibitor tested [150]. Thus, for example ABT-888 (veliparib) inhibited recombinant and intracellular PARP-1 activity and was also toxic to both oxic and hypoxic cells. This PARP inhibitor radiosensitize the human prostate carcinoma cell lines DU145 and 22RV1, as evidenced by the reduced clonogenic survival followed by ionizing radiation exposure (Stanley, 2008). Further support for the utilization of ABT-888 in combination therapy comes from studies showing that ABT-888 enhanced the effects of ionizing radiation in DU145 and PC-3 cells [151]. Interestingly, only PC-3 cells undergo enlarged flat morphology and positive staining for SA-p-Gal, and significant overexpression of p21, hallmarks of cell senescence. These findings were confirmed using PC-3 tumor xenografts in which tumor growth was delayed and presented a senescent phenotype. These results appear to indicate that combined ionizing radiation and PARP inhibition may improve therapeutic response in specific types of prostate cancer.

Function

Acceptor proteins

ABT888 (Veliparib)

Enhances cell death and tumor growth delay in irradiated cancer

models

5-AIQ hydrochloride

Decreases expression of inflammatory mediators activated by

neutrophils

3-Methil-5-AIQ hydrochloride l

Therapeutic benefits on myocardial infarction, ischaemia-reperfusion

of the liver and kidney, heart transplantation, and acute lung

inflammation

3-Aminobenzamide

Potentiate anticancer therapy

4-Amino-1,8-naphthalimide

Radiation sensitizer

Benzamide

Neuroprotectant

3-(4-Chlorophenyl)quinoxaline-5-carboxamide

Ameliorates methamphetamine-induced dopaminergic

neurotoxicity

(3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-

Reduces pre-neoplastic foci, expression of pre-neoplastic markers,

isoquinolinone DPQ

and pro-inflammatory genes in hepatocarcinomas

DR2313

Neuroprotectan

EB-47.dihydrochloride.dihydrate

Antioxidant

4-Hydroxyquinazoline

Antioxidant

5-Iodo-6-amino-1,2-benzopyrone

Neuroprotectan

1,5-Isoquinolinediol

Reduces repair of DNA damaged

Minocycline hydrocloride

Anti-inflammatory and neuroprotectan

Nicotinamide

Chemo- and radio-sensitizer

NU1025

Neuroprotectant

6(5H)-Phenanthridinone

Immunosuppressant

PJ-34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-

Anti-inflammatory

N, N-dimethylacetamide.HCl]

TIQ-A

Neuroprotectant

Table 4. A panel of PARP inhibitors

Table 4. A panel of PARP inhibitors

The clinical experiences with PARP inhibitors are now focus on patients carrying mutations of the BRCA1 or BRCA2 genes, which have been linked to increased sensitivity to PARP-1 inhibitors. For example Olaparib has proved to be very efficient in patients with breast or ovarian cancer with germline mutations in these two genes [152-154]. Although mutations on BCRA2 mutations have a major impact on breast cancer growth, males carrying alteration on this gene also have a high risk of develop prostate cancer [153, 155]. Additional evidence has shown that impaired DNA repair might benefit from treatment with PARP inhibitors. In deed several evidences have proved that PARP inhibitors sensitize human prostate cancer cell lines [148, 149, 156]. It is also know that treatment with high doses of chemotherapy induces massive DNA damage leading to PARP-1 overactivation with the subsequent energy depletion and cell death of tumor cells that are highly resistant [157]. More recently, it was described that PARP-1 mediates the oncogenic EST transcription factor ERG, which is frequently observed in fusion to the androgen-regulated gene TMPRSS2 in a significant amount of prostate tumors [158]. PARP-1 inhibition (treatment with Olaparib) in this group of tumors increases expression of the ETS gene, which promotes accumulation of DNA damage. This study also demonstrated that ERG physically interacts with PARP-1 and DNA-PKCsPARP-1 and that PARP-1 has a critical role on ERG-mediated transition from high-grade prostatic intraepithelial neoplasia to invasive carcinoma [159]. These findings clearly showed that PARP-1 inhibition could potentially increase survival of patients with tumors ETS-positive. Interesting, Olaparib remained ineffective on tumors that did not show the gene fusion. Altogether this evidence support the enormous interest in stimulate the utilization of a new generation of relatively non-toxic, orally administered PARP inhibitors in a series of cancer in clinical trials to induce genomic instability and cell death, blocking the grow and spread of cancer cells. The fact that PARP inhibition is specific against prostate cancer cells is an exciting and promising therapy approach, in part, because they may cause less severe effects than traditional therapies or radiotherapy.

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