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1.
Anticancer Res ; 43(2): 653-662, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36697069

RESUMO

BACKGROUND/AIM: Olaparib was approved in 2014 by the European Medicines Agency (EMA) as maintenance treatment for patients with breast cancer gene (BRCA)-mutated platinum-sensitive relapsed high-grade epithelial ovarian cancer (EOC) following the results of the Study 19. We present the results of a national real-world study on the effectiveness of olaparib in relapsed BRCA-mutated EOC patients. PATIENTS AND METHODS: Patients with EOC, peritoneal, and/or fallopian-tube cancer treated with olaparib in a French Center between May 2014 and March 2017 were included. The primary end-point of the study was progression-free survival. RESULTS: Of the 128 patients analyzed, 89 were treated according to the EMA label. The median progression-free survival was 17.0 months. The most common treatment-related toxicity was fatigue. Treatment-related myelodysplastic syndrome (n=5) and a second cancer (n=1) were diagnosed. CONCLUSION: In this real-life setting, olaparib confirmed its efficacy and safety profile, as previously shown in clinical trials.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Estudos de Coortes , Ftalazinas/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética
3.
Sci Rep ; 13(1): 1456, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36702871

RESUMO

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), "Ru-PIP", with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Rutênio , Animais , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Rutênio/farmacologia , Rutênio/química , Substâncias Intercalantes , Peixe-Zebra , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/farmacologia , Ftalazinas/farmacologia , DNA , Linhagem Celular Tumoral
4.
PLoS One ; 18(1): e0281168, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36706121

RESUMO

Malignancy is often associated with therapeutic resistance and metastasis, usually arising after therapeutic treatment. These include radio- and chemo-therapies, which cause cancer cell death by inducing DNA double strand breaks (DSBs). However, it is still unclear how resistance to these DSBs is induced and whether it can be suppressed. Here, we show that DSBs induced by camptothecin (CPT) and radiation jeopardize genome stability in surviving cancer cells, ultimately leading to the development of resistance. Further, we show that cytosolic DNA, accumulating as a consequence of genomic destabilization, leads to increased cGAS/STING-pathway activation and, ultimately, increased cell migration, a precursor of metastasis. Interestingly, these genomic destabilization-associated phenotypes were suppressed by the PARP inhibitor Olaparib. Recognition of DSBs by Rad51 and genomic destabilization were largely reduced by Olaparib, while the DNA damage response and cancer cell death were effectively increased. Thus, Olaparib decreases the risk of therapeutic resistance and cell migration of cells that survive radio- and CPT-treatments.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Quebras de DNA de Cadeia Dupla , Ftalazinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , DNA , Fenótipo , Linhagem Celular Tumoral
5.
J Obstet Gynaecol ; 43(1): 2151883, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36484513

RESUMO

This study aimed to evaluate the efficacy and safety of olaparib for the treatment of advanced ovarian cancer. All studies that assessed the efficacy and safety of olaparib in advanced ovarian cancer were searched in PubMed, Embase, and Web of Science from their inception to 20 September 2022. The analysis included six studies and 2016 patients. Olaparib could significantly prolong the progression-free survival (PFS) of patients compared to that of the control group (HR = 0.49, 95% CI = 0.36 - 0.68). However, no statistically significant differences were detected in overall survival (OS) and objective response rate (ORR) between the olaparib and control groups. Olaparib treatment increased the number of grade ≥3 adverse events (AEs) in patients with advanced ovarian cancer compared with that in the control group. Olaparib significantly prolonged PFS in patients with advanced ovarian cancer; however, no statistically significant differences were detected in OS and ORR. In terms of safety, olaparib has manageable adverse effects.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Antineoplásicos/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma Epitelial do Ovário , Ftalazinas/efeitos adversos
8.
Cancer Discov ; 12(12): 2716-2717, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36317849

RESUMO

Alternating treatment with the WEE1 inhibitor adavosertib and the PARP inhibitor olaparib helps control the growth of cancers with DNA repair defects with less toxicity than concurrent drug administration, according to data from a phase Ib trial presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Tirosina Quinases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico
10.
Anticancer Res ; 42(11): 5257-5263, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36288893

RESUMO

BACKGROUND/AIM: Tumor cell lines are essential tools in understanding the molecular mechanisms underlying cancer biology and therapeutic responses. Poly (ADP-ribose) polymerase inhibitors (PARPi) kill tumor cells harboring pathogenic mutations of BRCA DNA repair-associated genes 1/2 (BRCA1/2) and are approved to treat ovarian and metastatic breast cancer. Loss of heterozygosity (LOH) of the wild-type BRCA1/2 locus is suspected to increase cellular response to PARPi. To better elucidate the molecular mechanisms underlying PARPi sensitivity and resistance, this study assessed the responses of various pathogenic BRCA1/2-mutant cell lines to the PARPi talazoparib. MATERIALS AND METHODS: Mutant cell lines were extracted and cultured from four surgically resected, human breast cancer specimens with different pathogenic BRCA1/2, one normal breast specimen and one ovarian cancer specimen. Mutation analysis was performed on all cell lines using genomic DNA extraction and polymerase chain reaction. Following treatment with talazoparib, cell growth was assessed using tetrazolium salt and half-maximal inhibitory concentration values were determined. RESULTS: A partial correlation between different variants of pathogenic BRCA1/2 mutation and talazoparib susceptibility was found, with five of the cell lines exhibiting sensitivity to talazoparib. The most sensitive cell-line to talazoparib had LOH for BRCA1, while the breast cancer cell line harboring BRCA2 LOH was resistant to talazoparib. CONCLUSION: This study suggests that LOH does not necessarily correlate with PARPi efficacy. These results lay a foundation for future studies to utilize these novel cell lines to further elucidate the underlying molecular mechanisms of PARPi resistance and reveal new potential drug targets.


Assuntos
Neoplasias da Mama , Ribose , Feminino , Humanos , Ribose/uso terapêutico , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Biomarcadores , Perda de Heterozigosidade , Sais de Tetrazólio , Difosfato de Adenosina
11.
Cell Rep ; 41(2): 111462, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36223740

RESUMO

Poly(ADP)ribosylation inhibitors (PARPis) are toxic to cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast cancer (BC). The PARPi olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARPi-related surge in NAD+ increases glycolysis, blunts oxidative phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in reactive oxygen species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo, the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARPi. In vivo blockade of the "don't-eat-me signal" with CD47 antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model.


Assuntos
Antígeno CD47 , Inibidores de Poli(ADP-Ribose) Polimerases , Difosfato de Adenosina , Linhagem Celular Tumoral , Macrófagos , NAD , Niacinamida , Fenótipo , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Espécies Reativas de Oxigênio
12.
Ann Oncol ; 33(12): 1250-1268, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36228963

RESUMO

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ftalazinas/efeitos adversos , Células Germinativas/patologia , Proteína BRCA1/genética
13.
Tumori ; 108(6): NP30-NP33, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36299234

RESUMO

BACKGROUND: Despite ongoing developments, pancreatic cancer remains one of the most difficult tumors to treat. Even the most effective chemotherapy regimens, only marginally improve the outcome of Pancreatic cancer patients, which rarely exceeds one year. A small subset of Pancreatic cancer patients, carriers of germline variants of BRCA1/2, are clinically relevant as therapeutic targets in pancreatic cancer, both for the first-line and maintenance therapy, as they are more responsive to platinum-based chemotherapy agents and PARP inhibitors. Though, a little is known about the efficacy of olaparib monotherapy in later lines, or in poor responders to platinum-based regimens. METHODS: We describe a case of a patient with pancreatic cancer harboring BRCA2 mutation, treated with radical surgery, adjuvant treatment and three different palliative chemotherapy regimens at disease recurrence (FOLFOX in first line with progression-free survival of five months, gemcitabine and nab-paclitaxel in the second line with progression-free survival of six months and FOLFIRI in the third line with progression-free survival of three months) before olaparib off-label treatment. RESULTS: Interestingly, the patient remained 10 months on olaparib treatment, without disease progression, and without any side effects from the treatment. CONCLUSION: In conclusion, this case highlights the clinically relevant progression-free survival with olaparib treatment in later line and the potential of better health-related quality of life in this small subset of Pancreatic cancer patients.


Assuntos
Neoplasias Ovarianas , Neoplasias Pancreáticas , Humanos , Feminino , Qualidade de Vida , Mutação em Linhagem Germinativa , Ftalazinas/uso terapêutico , Ftalazinas/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Proteína BRCA2/genética , Mutação
14.
Cell Death Dis ; 13(10): 909, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36307400

RESUMO

PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to progression-free survival, especially in patients either carrying BRCA1/2 mutations or harboring defects in the homologous recombination repair system. Yet, it remains uncertain which PARPi to apply and how to predict responders when platinum sensitivity is unknown. To shed light on the predictive power of genes previously suggested to be associated with PARPi response, we systematically reviewed the literature and identified 79 publications investigating a total of 93 genes. The top candidate genes were further tested using a comprehensive CRISPR-Cas9 mutagenesis screening in combination with olaparib treatment. Therefore, we generated six constitutive Cas9+ EOC cell lines and profiled 33 genes in a CRISPR-Cas9 cell competition assay using non-essential (AAVS1) and essential (RPA3 and PCNA) genes for cell fitness as negative and positive controls, respectively. We identified only ATM, MUS81, NBN, BRCA2, and RAD51B as predictive markers for olaparib response. As the major survival benefit of PARPi treatment was reported in platinum-sensitive tumors, we next assessed nine top candidate genes in combination with three PARPi and carboplatin. Interestingly, we observed similar dropout rates in a gene and compound independent manner, supporting the strong correlation of cancer cell response to compounds that rely on DNA repair for their effectiveness. In addition, we report on CDK12 as a common vulnerability for EOC cell survival and proliferation without altering the olaparib response, highlighting its potential as a therapeutic target in EOC.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Sistemas CRISPR-Cas/genética , Detecção Precoce de Câncer , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Homologia de Genes
15.
Medicine (Baltimore) ; 101(39): e30719, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36181052

RESUMO

RATIONALE: To date, there is no actionable gene has been discovered in hepatocellular carcinoma (HCC). Tumor cells with DNA damage response and repair (DDR) gene loss-of-function mutation is sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors and platinum chemotherapy in ovarian, prostate and pancreatic cancers. There is a case report demonstrated the efficacy of PARP inhibitor for BRCA2 mutation that belongs to DDR gene in HCC, which suggested the potential role of PARP inhibitor for HCC with DDR gene mutation. PATIENT CONCERNS: We reported a 44-year-old woman with non-viral HCC who was refractory to multiple treatment including target therapy, immunotherapy, and chemotherapy. The tumor tissue was submitted to next-generation sequencing using the commercially available ACTOnco®+ (ACT Genomics, Taiwan) assay that interrogates 440 and 31 cancer-related genes and fusion genes, respectively. DIAGNOSIS: A truncating mutation FANCA p.Q1307fs was also observed. The tumor was microsatellite stable and had low tumor mutational burden of 4.5 muts/Mb. INTERVENTIONS AND OUTCOMES: Given FANCA belongs to DDR genes, the inactivation evoked the idea of using PARP inhibitor and cisplatin. Therefore, the patient started to use olaparib combined with low-dose cisplatin (30 mg/m2, every 4 weeks) therapy in December 2019. Significant reduction in the tumor marker level in 1 month (PIVKA-II from 17,395 to 411 ng/dL) and follow-up CT scan showed stable disease. Her tumor did not progress until December 2020 with a progression-free survival of 12 months. LESSONS: We report the first case of FANCA-mutated HCC that responded well to olaparib and low-dose cisplatin. This addressed the potential therapeutic role of DDR gene mutation in HCC and the possible synergistic effect of PARP inhibitor and cisplatin. These findings highlight areas where further investigation and effort are needed.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenosina Difosfato Ribose , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Cisplatino/uso terapêutico , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Masculino , Mutação , Ftalazinas , Piperazinas , Platina , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
16.
Cell Death Dis ; 13(9): 826, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36163324

RESUMO

Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.


Assuntos
Ferroptose , Neoplasias Ovarianas , Proteínas Quinases Ativadas por AMP , Difosfato de Adenosina , Animais , Apoptose , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/genética , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética , Ribose/farmacologia , Ribose/uso terapêutico , Estearoil-CoA Dessaturase
17.
Int J Mol Sci ; 23(18)2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36142413

RESUMO

Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovarian cancer and compounds in preclinical research, and olaparib, a PARP inhibitor targeting DNA damage repair, is a promising approach. P8-D6 induces DNA damage that can be repaired by base excision repair or homologous recombination in which PARP plays a major role. This study analyzed benefits of combining P8-D6 and olaparib treatment in 2D and 3D cultures with ovarian cancer cells. Measurement of viability, cytotoxicity and caspase activity were used to assess therapy efficacy and to calculate the combination index (CI). Further DNA damage was quantified using the biomarkers RAD51 and γH2A.X. The combinational treatment led to an increased caspase activity and reduced viability. CI values partially show synergisms in combinations at 100 nM and 500 nM P8-D6. More DNA damage accumulated, and spheroids lost their membrane integrity due to the combinational treatment. While maintaining the same therapy efficacy as single-drug therapy, doses of P8-D6 and olaparib can be reduced in combinational treatments. Synergisms can be seen in some tested combinations. In summary, the combination therapy indicates benefits and acts synergistic at 100 nM and 500 nM P8-D6.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Carcinoma Epitelial do Ovário/tratamento farmacológico , Caspases/genética , Morte Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Instabilidade Genômica , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores da Topoisomerase
18.
Int J Mol Sci ; 23(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36142803

RESUMO

Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína BRCA1/genética , Carboplatina/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética
19.
Oxid Med Cell Longev ; 2022: 9029544, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105480

RESUMO

PHGDH attaches importance to serine biosynthesis in cancer cells and maintaining mitochondrial redox homeostasis. However, the role of PHGDH inhibitor CBR-5884 in cell ROS level and its downstream pathways has not been explored in epithelial ovarian cancer. Thus, we investigated the function and possible mechanism of PHGDH inhibitor CBR-5884 on epithelial ovarian cancer in vitro and in vivo. A2780, OVCAR3, and ES-2 were treated with CBR-5884 at different concentrations or different time points. Results showed that CBR-5884 inhibited epithelial ovarian cancer cell proliferation, migration, and invasion and increases cell ROS level. Meanwhile, CBR-5884 exerts antitumor effect through activating ROS/Wnt/ß-catenin pathway. Besides, CBR-5884 exerts antitumor effect in vivo. What's more, we explored the effect of CBR-5884 with or without PARP inhibitor Olaparib, which showed that the two together had a larger effect. In conclusion, PHGDH inhibitor CBR-5884 inhibits epithelial ovarian cancer proliferation, migration, and invasion through activating ROS/Wnt/ß-catenin pathway and plays a synergistic role with PARP inhibitor olaparib, which provided a theoretical basis for PHGDH inhibitor CBR-5884 in clinical treatment.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/patologia , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Espécies Reativas de Oxigênio/uso terapêutico , Via de Sinalização Wnt , beta Catenina/metabolismo
20.
J Biomed Sci ; 29(1): 70, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109724

RESUMO

BACKGROUND: Seaweed polysaccharides have been recommended as anticancer supplements and for boosting human health; however, their benefits in the treatment of triple-negative breast cancers (TNBCs) and improving immune surveillance remain unclear. Olaparib is a first-in-class poly (ADP-ribose) polymerase inhibitor. Oligo-Fucoidan, a low-molecular-weight sulfated polysaccharide purified from brown seaweed (Laminaria japonica), exhibits significant bioactivities that may aid in disease management. METHODS: Macrophage polarity, clonogenic assays, cancer stemness properties, cancer cell trajectory, glucose metabolism, the TNBC 4T1 cells and a 4T1 syngeneic mouse model were used to inspect the therapeutic effects of olaparib and Oligo-Fucoidan supplementation on TNBC aggressiveness and microenvironment. RESULTS: Olaparib treatment increased sub-G1 cell death and G2/M arrest in TNBC cells, and these effects were enhanced when Oligo-Fucoidan was added to treat the TNBC cells. The levels of Rad51 and programmed death-ligand 1 (PD-L1) and the activation of epidermal growth factor receptor (EGFR) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) facilitate drug resistance and TNBC metastasis. However, the combination of olaparib and Oligo-Fucoidan synergistically reduced Rad51 and PD-L1 levels, as well as the activity of EGFR and AMPK; consistently, TNBC cytotoxicity and stemness were inhibited. Oligo-Fucoidan plus olaparib better inhibited the formation of TNBC stem cell mammospheroids with decreased subpopulations of CD44high/CD24low and EpCAMhigh cells than monotherapy. Importantly, Oligo-Fucoidan plus olaparib repressed the oncogenic interleukin-6 (IL-6)/p-EGFR/PD-L1 pathway, glucose uptake and lactate production. Oligo-Fucoidan induced immunoactive and antitumoral M1 macrophages and attenuated the side effects of olaparib, such as the promotion on immunosuppressive and protumoral M2 macrophages. Furthermore, olaparib plus Oligo-Fucoidan dramatically suppressed M2 macrophage invasiveness and repolarized M2 to the M0-like (F4/80high) and M1-like (CD80high and CD86high) phenotypes. In addition, olaparib- and Oligo-Fucoidan-pretreated TNBC cells resulted in the polarization of M0 macrophages into CD80(+) M1 but not CD163(+) M2 macrophages. Importantly, olaparib supplemented with oral administration of Oligo-Fucoidan in mice inhibited postsurgical TNBC recurrence and metastasis with increased cytotoxic T cells in the lymphatic system and decreased regulatory T cells and M2 macrophages in tumors. CONCLUSION: Olaparib supplemented with natural compound Oligo-Fucoidan is a novel therapeutic strategy for reprogramming cancer stemness, metabolism and the microenvironment to prevent local postsurgical recurrence and distant metastasis. The combination therapy may advance therapeutic efficacy that prevent metastasis, chemoresistance and mortality in TNBC patients.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Proteínas Quinases Ativadas por AMP , Adenosina/farmacologia , Difosfato de Adenosina/farmacologia , Difosfato de Adenosina/uso terapêutico , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Antígeno B7-H1 , Linhagem Celular Tumoral , Suplementos Nutricionais , Molécula de Adesão da Célula Epitelial , Receptores ErbB , Pontos de Checagem da Fase G2 do Ciclo Celular , Glucose , Humanos , Interleucina-6 , Lactatos/farmacologia , Lactatos/uso terapêutico , Camundongos , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Polissacarídeos/uso terapêutico , Ribose/farmacologia , Ribose/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
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