NAMPT/PBEF1 enzymatic activity is indispensable for myeloma cell growth and osteoclast activity.
Experimental hematology
Multiple myeloma (MM) cells typically grow in focal lesions, stimulating osteoclasts that destroy bone and support MM. Osteoclasts and MM cells are hypermetabolic. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is not only essential for cellular metabolism; it also affects activity of NAD-dependent enzymes, such as PARP-1 and SIRT-1. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin, encoded by PBEF1) is a rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide. Coculture of primary MM cells with osteoclasts induced PBEF1 upregulation in both cell types. PBEF1 expression was higher in experimental myelomatous bones than in nonmyelomatous bone and higher in MM patients' plasma cells than in healthy donors' counterparts. APO866 is a specific PBEF1 inhibitor known to deplete cellular NAD(+). APO866 at low nanomolar concentrations inhibited growth of primary MM cells or MM cell lines cultured alone or cocultured with osteoclasts and induced apoptosis in these cells. PBEF1 activity and NAD(+) content were reduced in MM cells by APO866, resulting in lower activity of PARP-1 and SIRT-1. The inhibitory effect of APO866 on MM cell growth was abrogated by supplementation of extracellular NAD(+) or NAM. APO866 inhibited NF-κB activity in osteoclast precursors and suppressed osteoclast formation and activity. PBEF1 knockdown similarly inhibited MM cell growth and osteoclast formation. In the SCID-rab model, APO866 inhibited growth of primary MM and H929 cells and prevented bone disease. These findings indicate that MM cells and osteoclasts are highly sensitive to NAD(+) depletion and that PBEF1 inhibition represents a novel approach to target cellular metabolism and inhibit PARP-1 and bone disease in MM.
10.1016/j.exphem.2013.02.008
Targeting poly (ADP-ribose) polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells.
Huang He,Cao Yang,Wei Wei,Liu Wei,Lu Shao-Yong,Chen Yu-Bao,Wang Yan,Yan Hua,Wu Ying-Li
PloS one
Despite recent pharmaceutical advancements in therapeutic drugs, multiple myeloma (MM) remains an incurable disease. Recently, ploy(ADP-ribose) polymerase 1 (PARP1) has been shown as a potentially promising target for MM therapy. A previous report suggested bufalin, a component of traditional Chinese medicine ("Chan Su"), might target PARP1. However, this hypothesis has not been verified. We here showed that bufalin could inhibit PARP1 activity in vitro and reduce DNA-damage-induced poly(ADP-ribosyl)ation in MM cells. Molecular docking analysis revealed that the active site of bufalin interaction is within the catalytic domain of PAPR1. Thus, PARP1 is a putative target of bufalin. Furthermore, we showed, for the first time that the proliferation of MM cell lines (NCI-H929, U266, RPMI8226 and MM.1S) and primary CD138(+) MM cells could be inhibited by bufalin, mainly via apoptosis and G2-M phase cell cycle arrest. MM cell apoptosis was confirmed by apoptotic cell morphology, Annexin-V positive cells, and the caspase3 activation. We further evaluated the role of PARP1 in bufalin-induced apoptosis, discovering that PARP1 overexpression partially suppressed bufalin-induced cell death. Moreover, bufalin can act as chemosensitizer to enhance the cell growth-inhibitory effects of topotecan, camptothecin, etoposide and vorinostat in MM cells. Collectively, our data suggest that bufalin is a novel PARP1 inhibitor and a potentially promising therapeutic agent against MM alone or in combination with other drugs.
10.1371/journal.pone.0066130
2,4-Dihydroxy-3'-methoxy-4'-ethoxychalcone suppresses cell proliferation and induces apoptosis of multiple myeloma the PI3K/akt/mTOR signaling pathway.
Pharmaceutical biology
Kom. (Fabaceae), a commonly used folk medicine, has been found to possess antitumor effects. However, the antiproliferative effect of 2,4-dihydroxy-3'-methoxy-4'-ethoxychalcone (DMEC) derived from against multiple myeloma (MM) has never been investigated. This study systematically evaluates the antiproliferative effect of DMEC against MM cells. The antiproliferative effect of DMEC (1, 2, 4, 8, 16, 32, and 64 μM) on MM cells lines, including RPMI8226, MM.1S, and U266, was examined using Cell counting kit-8 (CCK-8) assay after 24 h incubation. The proapoptotic effect of DMEC (20 μM) was determined using fluorescent microscope and flow cytometer, and its possible underlying mechanisms were further studied by using western blotting analysis. The half maximal inhibitory concentrations (IC) of DMEC on RPMI8226, MM.1S, and U266 cells were calculated as 25.97, 18.36, and 15.02 μM, respectively. The inhibitory effect of DMEC on MM cells was related to mitochondria-mediated apoptosis upregulation of the cleaved-caspase-3 (C-3), cleaved-caspase-9 (C-9), Bad, and cytochrome C (Cyto C), but downregulation of the Bcl-2 and poly ADP-ribose polymerase (PARP). Furthermore, DMEC (5, 10, and 20 μM) reduced the expression of phosphatidylinositol-3-kinase (PI3K), phosphorylated (p)-protein kinase B (Akt), and p-mammalian target of rapamycin (p-mTOR), which were further evidenced by pretreatment with IGF-1, a PI3K activator. Collectively, our results indicate that the DMEC could be treated as a new candidate for treatment of multiple myeloma in the future. Also, an study is warranted in the future.
10.1080/13880209.2019.1662814
Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?
Pawlyn Charlotte,Loehr Andrea,Ashby Cody,Tytarenko Ruslana,Deshpande Shayu,Sun James,Fedorchak Kyle,Mughal Tariq,Davies Faith E,Walker Brian A,Morgan Gareth J
Leukemia
PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.
10.1038/s41375-018-0017-0
Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.
Samur Mehmet Kemal,Fulciniti Mariateresa,Aktas Samur Anil,Bazarbachi Abdul Hamid,Tai Yu-Tzu,Prabhala Rao,Alonso Alejandro,Sperling Adam S,Campbell Timothy,Petrocca Fabio,Hege Kristen,Kaiser Shari,Loiseau Hervé Avet,Anderson Kenneth C,Munshi Nikhil C
Nature communications
BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
10.1038/s41467-021-21177-5
Influence of PJ34 on the genotoxicity induced by melphalan in human multiple myeloma cells.
Xiong Ting,Chen Xiaoqiong,Wei Heng,Xiao Hui
Archives of medical science : AMS
INTRODUCTION:The aim of this study was to evaluate the potential biological activity of N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride (PJ34) on the genotoxicity induced by melphalan in human multiple myeloma cells. MATERIAL AND METHODS:The inhibitory effects of the drugs on the growth of RPMI8226 cells were determined by Cell Counting Kit-8 (CCK-8) assay. The expression of Fanconi anemia/breast cancer (FA/BRCA) pathway related genes was determined by western blot analysis. Cell cycle phase and apoptosis were analyzed by flow cytometry. Coadministration of PJ34 and melphalan had additional effects on cell cycle distribution and enhanced apoptosis of RPMI8226 cells. PJ34 plus melphalan inhibited cell-cycle progression, as evidenced by the increased proportion of cells in the G2/M phase with the decreasing proportion of cells in the G0/1 and S phases. RESULTS:However, no significant synergistic effect of PJ34 and melphalan on cell proliferation was observed. These effects were accompanied by inhibition of the FA/BRCA pathway by downregulation of Fanconi D2 (FANCD2) protein expression. The results showed that treatment with 60 µmol/l of PJ34 previously to melphalan administration increased cell apoptosis. Pretreatment also caused cell cycle arrest. CONCLUSIONS:This study suggests that enhancement of melphalan efficacy may be best achieved by the poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor PJ34. The effects of PJ34 are associated with inhibition of the FA/BRCA pathway, increased apoptosis percentage, and G2/M cell cycle arrest. Administration of PJ34 has been shown to protect DNA from damage induced by melphalan. This corroborates the biological activities of PJ34 and points to the need for further studies.
10.5114/aoms.2014.43164
Targeting poly (ADP) ribose polymerase I (PARP-1) and PARP-1 interacting proteins for cancer treatment.
Sakamoto-Hojo Elza T,Balajee Adayabalam S
Anti-cancer agents in medicinal chemistry
Cancer is a disease of uncontrolled cellular proliferation. Chemotherapy and radiation therapy are the two main modalities for cancer treatment. However, some cancer types have been found to be refractory to these treatments. Additionally, certain chemicals that are used in clinical trials produce high cytotoxicity as a secondary effect. Hence, current research is focused on finding ways by which cancer cells can be specifically sensitized to apoptotic death with minimal or no secondary effects on normal healthy cells. Since the resistance of cancer cells to DNA damaging agents stems from the modulation of DNA repair pathways, pharmacological inhibition of these pathways has been emerging as an effective tool for cancer treatment. Inhibition of key proteins involved in the molecular cascade of DNA damage detection and repair such as poly (ADP) ribose polymerase I (PARP-1) and its interacting proteins [DNA dependent protein kinase (DNA-PK) and Cockayne syndrome group B (CSB)] has recently proven to be successful for the treatment of various types of cancer cells and tumor xenografts in vitro. This review summarizes some of the recent findings and the potential application of DNA repair inhibitors in cancer treatment.
10.2174/187152008784220302
The antimitotic potential of PARP inhibitors, an unexplored therapeutic alternative.
Iglesias Pablo,Costoya Jose A
Current topics in medicinal chemistry
ADP-ribosylation or PARsylation is one of the most abundant modifications of proteins and DNA. Although the usual context for PARsylation involves the detection and repair of DNA damage in the cell, poly(ADP-ribose) polymerases are known to regulate a number of biological processes besides maintaining genome integrity. One of these processes is the assembly and maintenance of the mitotic spindle where the presence of PARP-1 and tankyrase 1 (TNKS1), two of the best-characterized members of the PARP superfamily, is of critical importance. Here, we recapitulate the biological implications of the absence of poly(ADP-ribose) polymerases and depletion of PARsylation occurrence in mitosis in order to better understand the antimitotic effects of PARP inhibitors. In this regard, we also present an overview of the existing and more relevant molecules, with a special attention to the historical development of their pharmacological properties and structures, as well as a brief summary of clinical trials involving PARP inhibitors.
Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function.
Cell death and differentiation
Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD. Hence, mice lacking PARP-1 or PARP-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that PARP-1 and PARP-2 have on the cellular response to DNA damage. Failure to mount a proper response culminates in cell death. Accordingly, PARP inhibitors are emerging as promising drugs in cancer therapy. However, the full impact of these inhibitors on immunity, including B-cell antibody production, remains elusive. Given that mice carrying dual PARP-1 and PARP-2 deficiency develop early embryonic lethality, we crossed PARP-1-deficient mice with mice carrying a B-cell-conditional PARP-2 gene deletion. We found that the resulting dually PARP-1 and PARP-2-deficient mice had perturbed bone-marrow B-cell development as well as profound peripheral depletion of transitional and follicular but not marginal zone B-cells. Of note, bone-marrow B-cell progenitors and peripheral mature B-cells were conserved in mice carrying either PARP-1 or PARP-2 deficiency. In dually PARP-1 and PARP-2-deficient mice, B-cell lymphopenia was associated with increased DNA damage and accentuated death in actively proliferating B-cells. Moreover, dual PARP-1 and PARP-2 deficiency impaired antibody responses to T-independent carbohydrate but not to T-dependent protein antigens. Notwithstanding the pivotal role of PARP-1 and PARP-2 in DNA repair, combined PARP-1 and PARP-2 deficiency did not perturb the DNA-editing processes required for the generation of a protective antibody repertoire, including Ig V(D)J gene recombination and IgM-to-IgG class switching. These findings provide key information as to the potential impact of PARP inhibitors on humoral immunity, which will facilitate the development of safer PARP-targeting regimens against cancer.
10.1038/s41418-019-0326-5
Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.
Moreno-Lama Lucia,Galindo-Campos Miguel A,Martínez Carlos,Comerma Laura,Vazquez Ivonne,Vernet-Tomas María,Ampurdanés Coral,Lutfi Nura,Martin-Caballero Juan,Dantzer Françoise,Quintela-Fandino Miguel,Ali Syed O,Jimeno Jaime,Yélamos José
Oncogene
Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis. Here, we bypassed the embryonic lethality of dually PARP-1/PARP-2-deficient mice by using a PARP-1-deficient mouse with a Cd4-promoter-driven deletion of PARP-2 in T cells to investigate the understudied role of these PARPs in the modulation of T cell responses against AT-3-induced breast tumors. We found that dual PARP-1/PARP-2-deficiency in T cells promotes tumor growth while single deficiency of each protein limited tumor progression. Analysis of tumor-infiltrating cells in dual PARP-1/PARP-2-deficiency host-mice revealed a global change in immunological profile and impaired recruitment and activation of T cells. Conversely, single PARP-1 and PARP-2-deficiency tends to produce an environment with an active and partially upregulated immune response. Our findings pinpoint opposite effects of single and dual PARP-1 and PARP-2-deficiency in modulating the antitumor response with an impact on tumor progression, and will have implications for the development of more selective PARP-centered therapies.
10.1038/s41388-020-1175-x
Cytotoxicity of anticancer drugs and PJ-34 (poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor) on HL-60 and Jurkat cells.
Stępnik Maciej,Spryszyńska Sylwia,Gorzkiewicz Anna,Ferlińska Magdalena
Advances in clinical and experimental medicine : official organ Wroclaw Medical University
BACKGROUND:The majority of the clinical trials with poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors were conducted or are ongoing in patients with solid tumors, while trials with leukemia patients are less frequent. Surprisingly scarce data is available on the combinatory effects of PARP inhibitors with DNA damaging antitumor drugs in leukemic cells (primary cells or established lines). OBJECTIVES:The aim of the present study was to assess the effect of PJ-34 (PARP-1 inhibitor) on the cytotoxicity of different antileukemic drugs with different DNA damaging mechanisms and potency (doxorubicin, etoposide, cytarabine and chlorambucil) in human leukemic Jurkat and HL-60 cells. MATERIAL AND METHODS:Different exposure scenarios were applied: 1) 72 h simultaneous incubation with PJ-34 (2.5 or 5 μM for Jurkat and HL-60 cells, respectively) and a drug used at a wide concentration range; 2) preincubation of the cells with PJ-34 for 24 h and then with a combination of PJ-34 + drug for an additional 48 h; 3) preincubation of the cells with the drug for 24 h with a subsequent incubation with a combination of PJ-34 + drug for an additional 48 h. Cytotoxicity was assessed using a WST-1 reduction test. RESULTS:It was determined that PJ-34, when used in all 3 scenarios, did not induce any significant enhancement of cytotoxicity of the drugs either in Jurkat or in HL-60 cells. CONCLUSIONS:Although the results do not confirm the beneficial effects of PARP inhibition in combination treatment of the leukemic cells, we propose that future studies including an additional step with the inhibition of DNA repair by homologous recombination should provide promising results.
10.17219/acem/60848
LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL.
Parvin Salma,Ramirez-Labrada Ariel,Aumann Shlomzion,Lu XiaoQing,Weich Natalia,Santiago Gabriel,Cortizas Elena M,Sharabi Eden,Zhang Yu,Sanchez-Garcia Isidro,Gentles Andrew J,Roberts Evan,Bilbao-Cortes Daniel,Vega Francisco,Chapman Jennifer R,Verdun Ramiro E,Lossos Izidore S
Cancer cell
Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL.
10.1016/j.ccell.2019.07.007
Regulation of poly(ADP-Ribose) polymerase 1 functions by post-translational modifications.
Piao Lianhua,Fujioka Kyoko,Nakakido Makoto,Hamamoto Ryuji
Frontiers in bioscience (Landmark edition)
The poly(ADP-ribose) polymerases (PARPs) catalyze poly(ADP-ribosyl)ation, a post-translational modification of proteins. This consists of the attachment of mono- or poly- (ADP)-ribose units from nicotinamide adenine dinucleotide (NAD) to specific polar residues of target proteins. PARP1 is the most abundant and best-characterized member of the family of PARP enzymes. PARP1 plays key roles in DNA repair, as well as a wide variety of cellular processes, including transcriptional regulation, chromatin modulation, cellular signaling pathway, inflammation, cellular stress responses and so on. Hence, PARP1 inhibitors have become a promising therapeutic approach for human diseases including cancer. Recent studies indicate that post-translational modifications (PTMs) such as phosphorylation, acetylation, and methylation are crucial for the regulation of PARP1 activity, and dysregulation of modifications on PARP1 is observed in human cancer. In this review, we describe the importance of PTMs to regulate the activity of PARP1, and the involvement of dysregulation of PTMs in human cancer.
10.2741/4578
HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.
Nature
The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells. After binding to genomic lesions, these enzymes use NAD to modify numerous proteins with mono- and poly(ADP-ribose) signals that are important for the subsequent decompaction of chromatin and the recruitment of repair factors. These post-translational modifications are predominantly serine-linked and require the accessory factor HPF1, which is specific for the DNA damage response and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues. Here we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from HPF1 and PARP1 or PARP2 . The assembly of this catalytic centre is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response. As HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.
10.1038/s41586-020-2013-6
Effect of poly(ADP-ribose)polymerase and DNA topoisomerase I inhibitors on the p53/p63-dependent survival of carcinoma cells.
Montariello Daniela,Troiano Annaelena,Di Girolamo Daniela,Beneke Sascha,Calabrò Viola,Quesada Piera
Biochemical pharmacology
Depending on their genetic background (p53(wt) versus p53(null)), carcinoma cells are more or less sensitive to drug-induced cell cycle arrest and/or apoptosis. Among the members of the p53 family, p63 is characterized by two N-terminal isoforms, TAp63 and ΔNp63. TAp63 isoform has p53-like functions, while ΔNp63 acts as a dominant negative inhibitor of p53. We have previously published that TAp63 is involved in poly(ADP-ribose)polymerase-1 (PARP-1) signaling of DNA damage deriving from DNA topoisomerase I (TOP I) inhibition in carcinoma cells. In the present study, we treated MCF7 breast carcinoma cells (p53(+)/ΔNp63(-)) or SCC022 (p53(-)/ΔNp63(+)) squamous carcinoma cells with the TOP I inhibitor topotecan (TPT) and the PJ34 PARP inhibitor, to compare their effects in the two different cell contexts. In MCF7 cells, we found that PJ34 addition reverts TPT-dependent PARP-1 auto-modification and triggers caspase-dependent PARP-1 proteolysis. Moreover, TPT as single agent stimulates p53(ser15) phosphorylation, p53 PARylation and occupancy of the p21WAF promoter by p53 resulting in an increase of p21WAF expression. Interestingly, PJ34 in combination with TPT enhances p53 occupancy at the BAX promoter and is associated with increased BAX protein level. In SCC022 cells, instead, TPT+PJ34 combined treatment reduces the level of the anti-apoptotic ΔNp63α protein without inducing apoptosis. Remarkably, in such cells, either exogenous p53 or TAp63 can rescue the apoptotic program in response to the treatment. All together our results suggest that in cancer cells PARP inhibitor(s) can operate in the choice between growth arrest and apoptosis by modulating p53 family-dependent signal.
10.1016/j.bcp.2015.01.012
Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent.
Nguyen Diana,Zajac-Kaye Maria,Rubinstein Larry,Voeller Donna,Tomaszewski Joseph E,Kummar Shivaani,Chen Alice P,Pommier Yves,Doroshow James H,Yang Sherry X
Cell cycle (Georgetown, Tex.)
Targeting DNA repair with poly(ADP-ribose) polymerase (PARP) inhibitors has shown a broad range of anti-tumor activity in patients with advanced malignancies with and without BRCA deficiency. It remains unclear what role p53 plays in response to PARP inhibition in BRCA-proficient cancer cells treated with DNA damaging agents. Using gene expression microarray analysis, we find that DNA damage response (DDR) pathways elicited by veliparib (ABT-888), a PARP inhibitor, plus topotecan comprise the G1/S checkpoint, ATM, and p53 signaling pathways in p53-wildtype cancer cell lines and BRCA1, BRCA2 and ATR pathway in p53-mutant lines. In contrast, topotecan alone induces the G1/S checkpoint pathway in p53-wildtype lines and not in p53-mutant cells. These responses are coupled with G2/G1 checkpoint effectors p21(CDKN1A) upregulation, and Chk1 and Chk2 activation. The drug combination enhances G2 cell cycle arrest, apoptosis and a marked increase in cell death relative to topotecan alone in p53-wildtype and p53-mutant or -null cells. We also show that the checkpoint kinase inhibitor UCN-01 abolishes the G2 arrest induced by the veliparib and topotecan combination and further increases cell death in both p53-wildtype and -mutant cells. Collectively, PARP inhibition by veliparib enhances DDR and cell death in BRCA-proficient cancer cells in a p53-dependent and -independent fashion. Abrogating the cell-cycle arrest induced by PARP inhibition plus chemotherapeutics may be a strategy in the treatment of BRCA-proficient cancer.
10.4161/cc.10.23.18170
Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.
Du Yi,Yamaguchi Hirohito,Wei Yongkun,Hsu Jennifer L,Wang Hung-Ling,Hsu Yi-Hsin,Lin Wan-Chi,Yu Wen-Hsuan,Leonard Paul G,Lee Gilbert R,Chen Mei-Kuang,Nakai Katsuya,Hsu Ming-Chuan,Chen Chun-Te,Sun Ye,Wu Yun,Chang Wei-Chao,Huang Wen-Chien,Liu Chien-Liang,Chang Yuan-Ching,Chen Chung-Hsuan,Park Morag,Jones Philip,Hortobagyi Gabriel N,Hung Mien-Chie
Nature medicine
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.
10.1038/nm.4032
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes.
Gaymes Terry J,Shall Sydney,MacPherson Lee J,Twine Natalie A,Lea Nicholas C,Farzaneh Farzin,Mufti Ghulam J
Haematologica
UNLABELLED:Background Aberrant or impaired repair of double-strand DNA breaks is a common feature of de novo acute myeloid leukemia and myelodysplastic syndromes. Since poly (ADP-ribose) polymerase (PARP) inhibitors have been recently shown to selectively target cells with defects in double-strand DNA repair, the aim of this study was to explore the possibility of exploiting defects in DNA repair in leukemic cells using PARP inhibitors. DESIGN AND METHODS:Leukemic cell lines were exposed to various PARP inhibitors alone and in combination with non-cytotoxic concentrations of DNA methyltransferase inhibitor, 5' aza-2'-deoxycytidine and/or the histone deacetylase inhibitor, MS275, to test for potentiation of apoptosis with these agents. RESULTS:PARP inhibitors, KU-0058948 and PJ34, induced cell cycle arrest and apoptosis of primary myeloid leukemic cells and myeloid leukemic cell lines in vitro. Immunofluorescence analysis also revealed that PARP inhibitor sensitivity in these leukemic cells was due to a defect in homologous recombination DNA repair. Addition of 5' aza-2'-deoxycytidine failed to increase the cytotoxicity of PARP inhibitors. In contrast, MS275 potentiated the cytotoxic effect of KU-0058948 and PJ34 in all PARP inhibitor-sensitive leukemic cells. Immunofluorescence analysis supported the idea that histone deacetylase inhibitors potentiate cytotoxicity by inhibiting DNA repair processes. Conclusions On the basis of the data presented here, we suggest that PARP inhibitors can potentially exploit defects in double-strand DNA break repair in leukemic cells, paving the way for testing the therapeutic potential of these agents in myelodysplastic syndromes and acute myeloid leukemia.
10.3324/haematol.2008.001933
Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer.
García-Parra Jetzabel,Dalmases Alba,Morancho Beatriz,Arpí Oriol,Menendez Silvia,Sabbaghi MohammadA,Zazo Sandra,Chamizo Cristina,Madoz Juan,Eroles Pilar,Servitja Sonia,Tusquets Ignasi,Yelamos Jose,Lluch Ana,Arribas Joaquin,Rojo Federico,Rovira Ana,Albanell Joan
European journal of cancer (Oxford, England : 1990)
AIM:Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies. METHODS:We tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells. RESULTS:In a panel of four HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab had greater DNA damage than cells exposed to each agent alone. Mechanistic exploratory assays showed that trastuzumab downmodulated the homologous recombination protein proliferating cell nuclear antigen (PCNA). Combination treatment in the BT474 xenograft model resulted in enhanced growth inhibition, reduced tumour cell proliferation, and increased DNA damage and apoptosis. CONCLUSION:Taken together, our results show that PARP inhibition has antitumour effects and increases trastuzumab activity in HER2 overexpressing breast cancer. These findings make this novel combination a promising strategy for clinical development.
10.1016/j.ejca.2014.07.004
Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases.
Thapa Komal,Khan Heena,Sharma Uma,Grewal Amarjot Kaur,Singh Thakur Gurjeet
Life sciences
AIMS:Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors. MATERIALS AND METHODS:A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases. KEY FINDINGS:Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated. SIGNIFICANCE:In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases.
10.1016/j.lfs.2020.118975
Inhibition of poly(ADP-ribose) polymerase 1 protects against acute myeloid leukemia by suppressing the myeloproliferative leukemia virus oncogene.
Wang Lingbo,Cai Weili,Zhang Wei,Chen Xueying,Dong Wenqian,Tang Dongqi,Zhang Yun,Ji Chunyan,Zhang Mingxiang
Oncotarget
An abnormal expression of poly(ADP-ribose) polymerase 1 (PARP-1) has been described in many tumors. PARP-1 promotes tumorigenesis and cancer progression by acting on different molecular pathways. PARP-1 inhibitors can be used with radiotherapy or chemotherapy to enhance the susceptibility of tumor cells to the treatment. However, the specific mechanism of PARP-1 in acute myeloid leukemia (AML) remains unknown. Our study showed that expression of PARP-1 was upregulated in AML patients. PARP-1 inhibition slowed AML cell proliferation, arrested the cell cycle, induced apoptosis in vitro and improved AML prognosis in vivo. Mechanistically, microarray assay of AML cells with loss of PARP-1 function revealed that the myeloproliferative leukemia virus oncogene (MPL) was significantly downregulated. In human AML samples, MPL expression was increased, and gain-of-function and loss-of-function analysis demonstrated that MPL promoted cell growth. Moreover, PARP-1 and MPL expression were positively correlated in AML samples, and their overexpression was associated with an unfavorable prognosis. Furthermore, PARP-1 and MPL consistently acted on Akt and ERK1/2 pathways, and the anti-proliferative and pro-apoptotic function observed with PARP-1 inhibition were reversed in part via MPL activation upon thrombopoietin stimulation or gene overexpression. These data highlight the important function of PARP-1 in the progression of AML, which suggest PARP-1 as a potential target for AML treatment.
10.18632/oncotarget.4748