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Cancers
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PARPs in Cancer
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PARPs in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (1 August 2021) | Viewed by 18873

Special Issue Editor

Dr. Anderson Ryan

E-Mail Website
Guest Editor
Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Interests: DNA damage response; radiobiology; synthetic lethality; lung cancer; ionizing radiation; normal tissue responses

Special Issue Information

Dear Colleagues,

The key role of Poly (ADP-ribose) polymerases (PARPs) in the DNA damage response to single-stranded breaks has been recognized for several decades. However, interest in PARPs as a target in cancer therapy was greatly increased with the discovery that PARP inhibition is synthetically lethal with defects in homologous recombination, most notably in breast and ovarian cancers with loss of BRCA function. This led to the rapid development and regulatory approval of several PARP inhibitors that are now established in clinical use.

Despite this early success, there are still major unanswered questions about the role of PARPs in cancer, and how to further develop PARP inhibitors beyond their use in BRCA-deficient disease. This Special Issue will highlight both the roles of PARP family members in cancer and approaches that aim to expand our biological understanding and future clinical potential of PARP inhibitors either as a monotherapy or in combination with established or emerging anti-cancer agents.

Prof. Anderson Joseph Ryan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PARP-1
  • PARP-2
  • BRCA1
  • BRCA2
  • DNA damage response
  • homologous recombination
  • base excision repair
  • breast cancer
  • ovarian cancer

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Published Papers (4 papers)

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Research

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18 pages, 4330 KiB  
Article
Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells
by Yi Xie, Linbo Wang, Mohammad A. Khan, Anne W. Hamburger, Wei Guang, Antonino Passaniti, Kashif Munir, Douglas D. Ross, Michael Dean and Arif Hussain
Cancers 2021, 13(4), 633; https://doi.org/10.3390/cancers13040633 - 5 Feb 2021
Cited by 13 | Viewed by 3272
Abstract
We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) [...] Read more.
We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC. Full article
(This article belongs to the Special Issue PARPs in Cancer)
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Review

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15 pages, 622 KiB  
Review
PARP Inhibitors in Combination with Radiotherapy: To Do or Not to Do?
by Amelia Barcellini, Pierre Loap, Kazutoshi Murata, Riccardo Villa, Youlia Kirova, Noriyuki Okonogi and Ester Orlandi
Cancers 2021, 13(21), 5380; https://doi.org/10.3390/cancers13215380 - 27 Oct 2021
Cited by 25 | Viewed by 2913
Abstract
Background: Despite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) is unclear. Aim: We conducted a literature analysis with the aim to evaluate the efficacy and safety profile of a combination [...] Read more.
Background: Despite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) is unclear. Aim: We conducted a literature analysis with the aim to evaluate the efficacy and safety profile of a combination with RT and PARP-I. Method: The key issues for the current review were expressed in two questions according to the Population, Intervention, Control, Outcome (PICO) criteria: 1. What is the outcome and 2. What is the toxicity in patients treated with a combination of PARP-I and RT for a newly diagnosed or recurrent tumors? Results: A total of 12 clinical studies met the inclusion criteria including seven single-arm dose-escalation phase I studies, two phase II (two- and three-arms controlled trials) trials, one parallel-arm phase I study, and two phase I/II studies published between 2015 and 2021. RT was performed with photon beams and several schedules according to the clinical situation. The acute toxicity ≥ grade 3 ranged between 25% and >96%, which was divided into hematological or non-hematological adverse events. Conclusions: despite the heterogeneity of the evaluated patient populations and tumor types, and the limited number of the studies, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear. Full article
(This article belongs to the Special Issue PARPs in Cancer)
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21 pages, 1796 KiB  
Review
The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions
by Máté A. Demény and László Virág
Cancers 2021, 13(9), 2057; https://doi.org/10.3390/cancers13092057 - 24 Apr 2021
Cited by 18 | Viewed by 4625
Abstract
Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets [...] Read more.
Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets DNA damage-responsive PARPs (PARP1–3). However, the biological roles of PARP family member enzymes are broad; therefore, the effects of PARPis should be viewed in a much wider context, which includes complex effects on all known hallmarks of cancer. In the companion paper (part 1) to this review, we presented the fundamental roles of PARPs in intrinsic cancer cell hallmarks, such as uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, replicative immortality, and reprogrammed metabolism. In the second part of this review, we present evidence linking PARPs to cancer-associated inflammation, anti-cancer immune response, invasion, and metastasis. A comprehensive overview of the roles of PARPs can facilitate the identification of novel cancer treatment opportunities and barriers limiting the efficacy of PARPi compounds. Full article
(This article belongs to the Special Issue PARPs in Cancer)
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28 pages, 3413 KiB  
Review
The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks
by Máté A. Demény and László Virág
Cancers 2021, 13(9), 2042; https://doi.org/10.3390/cancers13092042 - 23 Apr 2021
Cited by 43 | Viewed by 7039
Abstract
The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other [...] Read more.
The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms. Full article
(This article belongs to the Special Issue PARPs in Cancer)
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