Leveraging shape screening and molecular dynamics simulations to optimize PARP1-Specific chemo/radio-potentiators for antitumor drug design.

PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds. In step 2, hierarchical docking approach embedded in Schrödinger suite was employed to select compounds with good dock score, drug-likeness and MMGBSA score. Analysis supplemented with decomposition energy, molecular dynamics (MD) simulations and hydrogen bond frequency analysis, pinpointed that active site residues; H862, G863, R878, M890, Y896 and F897 are crucial for specific binding of ZINC001258189808 and ZINC000092332196 with PARP1 as compared to PARP2 and PARP3. The binding of ZINC000656130962, ZINC000762230673, ZINC001332491123, and ZINC000579446675 also revealed interaction involving two additional active site residues of PARP1, namely N767 and E988. Weaker or no interaction was observed for these residues with PARP2 and PARP3. This approach advances our understanding of PARP-1 specific inhibitors and their mechanisms of action, facilitating the development of targeted therapeutics.

NAD+-A Hub of Energy Metabolism in Heart Failure.

Heart failure is a condition where reduced levels of adenosine triphosphate (ATP) affect energy supply in myocardial cells. Nicotinamide adenine dinucleotide (NAD+) plays a crucial role as a coenzyme for electron transfer in energy metabolism. Decreased NAD+ levels in myocardial cells lead to inadequate ATP production and increased susceptibility to heart failure. Researchers are exploring ways to increase NAD+ levels to alleviate heart failure. Targets such as sirtuin2 (sirt2), sirtuin3 (sirt3), Poly (ADP-ribose) polymerase (PARP), and diastolic regulatory proteins are being investigated. NAD+ supplementation has shown promise, even in heart failure with preserved ejection fraction (HFpEF). By focusing on NAD+ as a central component of energy metabolism, it is possible to improve myocardial activity, heart function, and address energy deficiency in heart failure.

N,N-Dimethyl-anthranilic Acid from Calvatia nipponica Mushroom Fruiting Bodies Induces Apoptotic Effects on MDA-MB-231 Human Breast Cancer Cells.

Breast cancer ranks among the most prevalent malignancies affecting women worldwide, and apoptosis-targeting drugs are attractive candidates for the treatment of cancer. In the current study, we investigated the in vitro cytotoxicity of the mushroom Calvatia nipponica in human breast cancer cells (MDA-MB-231), identified potential antitumor compounds through bioactivity-guided isolation, and elucidated the antitumor, pro-apoptotic molecular mechanisms of the identified bioactive compounds. C. nipponica is edible when young, and it has been used as a food source as well as a traditional medicine in wound dressings. However, only a limited number of studies have reported its chemical composition and biological activities. In the screening test, the methanol extract of C. nipponica fruiting bodies exhibited cytotoxicity against MDA-MB-231 cells. Bioactivity-guided fractionation of the methanol (MeOH) extract and chemical investigation of the active fractions resulted in the isolation of fourteen compounds (1-14), including six alkaloids (1-3, 5, 7, and 8), two phenolic compounds (4 and 6), one fatty acid (9), and five steroids (10-14). The structures of the isolated compounds were determined using NMR spectroscopic methods, liquid chromatography-mass spectrometry, and comparison of data with previously reported values. The isolated compounds (1-14) were tested for cytotoxicity against MDA-MB-231 cells, where compound 1, i.e., N,N-dimethyl-anthranilic acid, exhibited the most significant cytotoxicity against MDA-MB-231 cells, with an IC50 value of 90.28 ± 4.23 µM and apoptotic cell death of 56.01% ± 2.64% at 100 µM. Treatment with compound 1 resulted in an upregulation of protein levels, including cleaved caspase-8, cleaved poly (ADP-ribose) polymerase, Bcl-2-associated X protein (Bax), cleaved caspase-3, cleaved caspase-9, Bad, and Cytochrome c, but decreased the levels of B-cell lymphoma 2 (Bcl-2). Overall, these results indicate that N,N-dimethyl-anthranilic acid (1) may have anti-breast cancer activity and is probably involved in the induction of apoptosis mediated by extrinsic and intrinsic signaling pathways.

Does oxidative DNA damage trigger histotoxic hypoxia via PARP1/AMP-driven mitochondrial ADP depletion-induced ATP synthase inhibition in Alzheimer's disease?

The low cerebral metabolic rate of oxygen despite the relatively preserved perfusion in Alzheimer's disease (AD) patients' medial temporal lobes suggest histotoxic hypoxia due to mitochondrial dysfunction that is independent of, but could precede, insulin resistance. Neuropathological, metabolomic, and preclinical evidence are consistent with the notion that this mitochondrial dysfunction may be contributed to by oxidative stress and DNA damage, leading to poly-(ADP-ribose)-polymerase-1 (PARP1) activation and consequent AMP accumulation, clogging of mitochondrial adenine nucleotide transporters (ANTs), matrix ADP deprivation, and ATP synthase inhibition. Complementary mechanisms may include mitochondrial-protein poly-ADP-ribosylation and mitochondrial-biogenesis suppression via PARPs outcompeting Sirtuin-1 (SIRT1) for nicotinamide-adenine-dinucleotide (NAD+).

Complementary CRISPR genome-wide genetic screens in PARP10-knockout and overexpressing cells identify synthetic interactions for PARP10-mediated cellular survival.

PARP10 is a mono-ADP-ribosyltransferase with multiple cellular functions, including proliferation, apoptosis, metabolism and DNA repair. PARP10 is overexpressed in a significant proportion of tumors, particularly breast and ovarian cancers. Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology. Here, we performed a series of CRISPR genome-wide loss-of-function screens in isogenic control and PARP10-overexpressing or PARP10-knockout cell lines, to identify genetic determinants of PARP10-mediated cellular survival. We found that PARP10-overexpressing cells rely on multiple DNA repair genes for survival, including ATM, the master regulator of the DNA damage checkpoint. Moreover, we show that PARP10 impacts the recruitment of ATM to nascent DNA upon replication stress. Finally, we identify the CDK2-Cyclin E1 complex as essential for proliferation of PARP10-knockout cells. Our work identifies a network of functionally relevant PARP10 synthetic interactions, and reveals a set of factors which can potentially be targeted in personalized cancer therapy.

Alloimperatorin activates apoptosis, ferroptosis, and oxeiptosis to inhibit the growth and invasion of breast cancer cells in vitro.

Breast cancer is the most common malignant tumour in women. Our research on alloimperatorin from Angelica dahurica showed that alloimperatorin inhibited breast cancer cell viability in a concentration- and time-dependent manner; it also showed that apoptosis and ferroptosis inhibitors significantly weakened the antisurvival effect of alloimperatorin. Alloimperatorin clearly induced breast cancer cell apoptosis and increased the activities of caspase-3, caspase-8, caspase-9, and poly (ADP-ribose) polymerase; it also caused significant mitochondrial shrinkage, promoted the accumulation of Fe2+, reactive oxygen species, and malondialdehyde, and significantly reduced mRNA and protein expression levels of SLC7A11 and GPX4, indicating that alloimperatorin induces ferroptosis. In addition, alloimperatorin significantly promoted Kelch-like ECH-associated protein 1 (Keap1) expression; although it did not affect the expression of PGAM5 (mitochondrial serine/threonine protein phosphatase) and apoptosis-inducing factor mitochondria associated 1 (AIFM1), it significantly reduced the phosphorylation level of AIFM1. After downregulating the expression of Keap1, PGAM5, or AIFM1, the inhibitory effect of alloimperatorin on cell viability was significantly weakened, indicating that alloimperatorin regulates the Keap1/PGAM5/AIFM1 pathway to promote oxeiptosis. Alloimperatorin significantly inhibited the invasion of breast cancer cells, while Keap1 siRNA or GPX4 overexpression vectors significantly enhanced cell invasion and effectively reversed the anti-invasive effect of alloimperatorin. Therefore, alloimperatorin induces breast cancer cell apoptosis, ferroptosis, and oxeiptosis, thereby inhibiting cell growth and invasion.

Inhibitors of PARP: Number crunching and structure gazing.

SignificancePARP is an important target in the treatment of cancers, particularly in patients with breast, ovarian, or prostate cancer that have compromised homologous recombination repair (i.e., BRCA-/-). This review about inhibitors of PARP (PARPi) is for readers interested in the development of next-generation drugs for the treatment of cancer, providing insights into structure-activity relationships, in vitro vs. in vivo potency, PARP trapping, and synthetic lethality.

Arachidin-1, a Prenylated Stilbenoid from Peanut, Induces Apoptosis in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is unresponsive to typical hormonal treatments, causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. The goal of this study was to assess cytotoxicity and apoptosis mechanisms of prenylated stilbenoids in TNBC cells. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3) are analogs of resveratrol (RES) produced in peanut upon biotic stress. The anticancer activity of A-1 and A-3 isolated from peanut hairy root cultures was determined in TNBC cell lines MDA-MB-231 and MDA-MB-436. After 24 h of treatment, A-1 exhibited higher cytotoxicity than A-3 and RES with approximately 11-fold and six-fold lower IC50, respectively, in MDA-MB-231 cells, and nine-fold and eight-fold lower IC50, respectively, in MDA-MB-436 cells. A-1 did not show significant cytotoxicity in the non-cancerous cell line MCF-10A. While A-1 blocked cell division in G2-M phases in the TNBC cells, it did not affect cell division in MCF-10A cells. Furthermore, A-1 induced caspase-dependent apoptosis through the intrinsic pathway by activating caspase-9 and PARP cleavage, and inhibiting survivin. In conclusion, A-1 merits further research as a potential lead molecule for the treatment of TNBC.

Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs.

The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.

Resveratrol Suppresses Annulus Fibrosus Cell Apoptosis through Regulating Oxidative Stress Reaction in an Inflammatory Environment.

During disc degeneration, the increase of inflammatory cytokines and decrease of disc cell density are two prominent features. Enhanced inflammatory reaction contributes to disc annulus fibrosus (AF) cell apoptosis. In this study, we investigated whether resveratrol can suppress AF cell apoptosis in an inflammatory environment. Rat disc AF cells were cultured in medium with or without tumor necrosis factor-α (TNF-α). Resveratrol was added along with the culture medium supplemented with TNF-α. Caspase-3 activity, cell apoptosis ratio, expression of apoptosis-associated molecules (Bcl-2, Bax, caspase-3, cleaved PARP, and cleaved caspase-3), reactive oxygen species (ROS) content, and the total superoxide dismutase (SOD) activity were measured. Our results showed that TNF-α significantly increased caspase-3 activity and AF cell apoptosis ratio and upregulated gene/protein expression of Bax, caspase-3, cleaved caspase-3, and cleaved PARP, whereas it downregulated the expression of Bcl-2. Moreover, TNF-α significantly increased ROS content but decreased the total SOD activity. Further analysis demonstrated that resveratrol partly attenuated the effects of TNF-α on AF cell apoptosis-associated parameters, decreased ROS content, and increased the total SOD activity in the AF cells treated with TNF-α. In conclusion, resveratrol attenuates inflammatory cytokine TNF-α-induced AF cell apoptosis through regulating oxidative stress reaction in vitro. This study sheds a new light on the protective role of resveratrol in alleviating disc degeneration.

Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions.

Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis-TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.

Noncanonical mono(ADP-ribosyl)ation of zinc finger SZF proteins counteracts ubiquitination for protein homeostasis in plant immunity.

Protein ADP-ribosylation is a reversible post-translational modification that transfers ADP-ribose from NAD+ onto acceptor proteins. Poly(ADP-ribosyl)ation (PARylation), catalyzed by poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolases (PARGs), which remove the modification, regulates diverse cellular processes. However, the chemistry and physiological functions of mono(ADP-ribosyl)ation (MARylation) remain elusive. Here, we report that Arabidopsis zinc finger proteins SZF1 and SZF2, key regulators of immune gene expression, are MARylated by the noncanonical ADP-ribosyltransferase SRO2. Immune elicitation promotes MARylation of SZF1/SZF2 via dissociation from PARG1, which has an unconventional activity in hydrolyzing both poly(ADP-ribose) and mono(ADP-ribose) from acceptor proteins. MARylation antagonizes polyubiquitination of SZF1 mediated by the SH3 domain-containing proteins SH3P1/SH3P2, thereby stabilizing SZF1 proteins. Our study uncovers a noncanonical ADP-ribosyltransferase mediating MARylation of immune regulators and underpins the molecular mechanism of maintaining protein homeostasis by the counter-regulation of ADP-ribosylation and polyubiquitination to ensure proper immune responses.

Enhancement of Anticancer Potential of Pterostilbene Derivative by Chalcone Hybridization.

Pterostilbene, a natural metabolite of resveratrol, has been indicated as a potent anticancer molecule. Recently, several pterostilbene derivatives have been reported to exhibit better anticancer activities than that of the parent pterostilbene molecule. In the present study, a series of pterostilbene derivatives were designed and synthesized by the hybridization of pterostilbene, chalcone, and cinnamic acid. The cytotoxic effect of these hybrid molecules was determined using two oral cancer cell lines, HSC-3 and OECM-1. (E)-3-(2-((E)-4-Hydroxystyryl)-4,6-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (4d), with IC50 of 16.38 and 18.06 µM against OECM-1 and HSC-3, respectively, was selected for further anticancer mechanism studies. Results indicated that compound 4d effectively inhibited cell proliferation and induced G2/M cell cycle arrest via modulating p21, cyclin B1, and cyclin A2. Compound 4d ultimately induced cell apoptosis by reducing the expression of Bcl-2 and surviving. In addition, cleavage of PARP and caspase-3 were enhanced following the treatment of compound 4d with increased dose. To conclude, a number of pterostilbene derivatives were discovered to possess potent anticancer potentials. Among them, compound 4d was the most active, more active than the parent pterostilbene.

PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling.

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

Olea europaea L. Flowers as a new promising anticancer natural product: phenolic composition, antiproliferative activity and apoptosis induction.

The aim of this study was to characterise phenolic compounds of olive flower obtained from Olive tree cultivar Chemlali and to investigate their anticancer effect on MCF-7 cells. Phenolic characterisation was determined using LC/MS-MS. Cytotoxicity of the extract was determined using MTT. Biochemical markers of apoptosis were evaluated by immunoblotting. Our results showed that olive flower contained significant amounts of phenolic compounds mainly flavonoids, secoiridoids and simple phenols. Furthermore, the phenolic extract exerted a significant reduction in MCF-7 cell viability (EC50 values equal to 220.8 µg/ml). Western blot analysis revealed the presence of the cleaved forms of Parp-1. The DAPI staining analysis demonstrated a significant reduction in the number of cells and a considerable change in the morphology of the treated cells. In conclusion, Olea europaea. L flower contained great amounts of different bio-phenols able to reduce the proliferative activity of breast cancer MCF-7 cells by the induction of apoptosis.

Methylsulfonylmethane sensitizes endometrial cancer cells to doxorubicin.

BACKGROUND: Methylsulfonylmethane (MSM) is a commonly used diet supplement believed to decrease the inflammation in joints and fastens recovery in osteoarthritis, gastric mucosal injury, or obesity-related disorders. It was also suggested that MSM might play a beneficial role in cancer treatment. PURPOSE: So far, the MSM might have a potentially beneficial effect in endometrial cancer (EC) treatment. STUDY DESIGN: This study evaluated the effect and usefulness of MSM in combinatory therapy with known drug doxorubicin (DOX). METHODS: The effect of combinational treatment of MSM and DOX on the induction of apoptosis was evaluated in EC cell lines (ISHIKAWA, MFE-296, MFE-280). RESULTS: We observed that MSM itself induces apoptosis in EC cell lines, and pre-treatment with MSM for 24 h increases the sensitivity of EC cells to DOX-induced apoptosis and DNA damage and that effect might be regulated by p42/44 (Erk1/2) MAPK and Akt (protein kinase B). CONCLUSION: These results for the first time show that MSM might act as a sensitizer of EC cells to known drugs, for which EC cells quickly acquire resistance. Graphical abstract.

Biochemical Evidence Indicates the Preventive Effect of Resveratrol and Nicotinamide in the Treatment of STZ-induced Diabetic Cataract.

PURPOSE: High glucose level is a strong initiator of both oxidative stress and DNA damage to various cellular proteins. This activates the poly ADP-ribose polymerase (PARP) enzyme, which is responsible for disturbing physiological energy metabolic homeostasis. The present study aimed to elucidate the association between stress and the PARP pathway by using resveratrol (RSV) and nicotinamide (NAM, PARP inhibitor) to treat diabetic cataract. METHOD: Albino rats were used for the experimental study. A single streptozotocin administration (55 mg/kg, i.p.) prompted diabetes in the animals. The experimental groups were the normal group (non-diabetic) and the diabetic groups: the diabetic control animals (group D), the diabetic animals treated with RSV at 40 mg/kg/day, i.p. (D+ RSV group), NAM at 100 and 300 mg/kg/day, i.p. (D+ NAM100, D+ NAM300 groups, respectively), and a combination of RSV and NAM i.p. (D+ RSV+NAM100 = Combi 1 group, D+ RSV+NAM300 = Combi 2 group). Glucose levels and the eyes were examined biweekly; various cataractogenic parameters in the lenses were examined after completion of the eight-week experimental protocol. RESULTS: Compared to diabetic control, RSV monotherapy significantly decreased hyperglycemia and other lenticular alterations. NAM at the high dose only showed beneficial effects without altering the blood glucose level, lenticular aldose reductase (AR) activity, and sorbitol content, primarily restored the lenticular NAD level and decreased oxidative stress in diabetic rats. These findings regarding NAM treatment indicate that a pathway other than the antioxidant defense system and the polyol pathway, which might be due to PARP inhibition, is involved in diabetic cataracts. Moreover, compared to RSV monotherapy, combination treatments were effective. CONCLUSION: These results indicate that hyperglycemia and oxidative-osmotic-nitrosative stress play central roles in the pathophysiology of diabetic cataracts. Moreover, our study also revealed that concurrent treatment with the RSV and NAM may prove useful in the pharmacotherapy of diabetes and its secondary complications such as cataract.

[Pt(O,O'-acac)(γ-acac)(DMS)]: Alternative Strategies to Overcome Cisplatin-Induced Side Effects and Resistance in T98G Glioma Cells.

Cisplatin (CDDP) is one of the most effective chemotherapeutic agents, used for the treatment of diverse tumors, including neuroblastoma and glioblastoma. CDDP induces cell death through different apoptotic pathways. Despite its clinical benefits, CDDP causes several side effects and drug resistance.[Pt(O,O'-acac)(γ-acac)(DMS)], namely PtAcacDMS, a new platinum(II) complex containing two acetylacetonate (acac) and a dimethylsulphide (DMS) in the coordination sphere of metal, has been recently synthesized and showed 100 times higher cytotoxicity than CDDP. Additionally, PtAcacDMS was associated to a decreased neurotoxicity in developing rat central nervous system, also displaying great antitumor and antiangiogenic activity both in vivo and in vitro. Thus, based on the knowledge that several chemotherapeutics induce cancer cell death through an aberrant increase in [Ca2+]i, in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca2+ dynamics in human glioblastoma T98G cells, applying a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, electron microscopy, Western blotting, qRT-PCR, and epifluorescent Ca2+ imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca2+]i and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca2+]i. These findings corroborate the use of PtAcacDMS as a promising approach to improve Pt-based chemotherapy against gliomas, either by inducing a chemosensitization or reducing chemoresistance in cell lineages resilient to CDDP treatment.

Long-term consumption of recycled cooking oil induces cell death and tissue damage.

Recycled cooking oil (RCO) is widely used in many small restaurants. However, the health risk posed by long-term consumption of RCO is unclear. In this study, C57 mice were treated with RCO for 34 weeks. Organ coefficients of the liver, stomach, and kidney were found to be decreased. H&E staining revealed overt lesions in the pancreas, liver, kidney, esophagus, duodenum, and ileum of RCO-treated mice. Immunohistochemistry showed significant DNA damage in the duodenum and ileum and apoptosis in the lungs of the RCO-treated mice. Immunoblotting showed elevated levels of γ-H2AX, Bcl-2/Bax, TNFα, cleaved Caspase-3 and poly ADP-ribose polymerase (PARP). Increased levels of lactate dehydrogenase (LDH) and decreased levels of succinate dehydrogenase (SDH) were also detected. These findings suggest that long-term consumption of RCO produces various toxicities in mice with important implications for humans. DNA damage followed by mitochondria-associated apoptosis, and necrosis is likely to contribute to the toxicities.

PARP inhibition as frontline therapy in ovarian cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been rapidly integrated into clinical practice for women with ovarian cancer. Currently, PARP inhibitors are approved as frontline maintenance treatment for patients with and without BRCA-associated cancers, and they are listed by the National Comprehensive Cancer Network (NCCN) as a treatment option for all high-grade serous and endometrioid cancers with or without bevacizumab. PARP inhibitors are also approved as maintenance treatment following a response to platinum-based therapy in the recurrent setting, irrespective of biomarker status. Additionally, PARP inhibitors are approved as third-line treatment and beyond in lieu of chemotherapy for patients with BRCA-associated cancers, and as fourth-line treatment and beyond for patients with platinum-sensitive homologous recombination-deficient tumors. They are also listed by the NCCN in combination with bevacizumab for the treatment of patients who have platinum-sensitive recurrent disease. The first part of this 2-part review focuses on the changing paradigm of frontline therapy options resulting from the recent approvals of PARP inhibitors; the second part considers the role of PARP inhibition in recurrent ovarian cancer.