The cell cycle checkpoint inhibitors in the treatment of leukemias

Rorà, Andrea Ghelli Luserna di; Iacobucci, Ilaria; Martinelli, Giovanni

doi:10.1186/s13045-017-0443-x

Cited by 59 publications

(46 citation statements)

References 122 publications

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“…In addition, as indicated by their ability to prevent digestion of plasmid DNA with BamHI restriction nuclease, the studied chromanone/flavanone analogues appear to be capable of intercalating with genomic DNA of cancer cells, thus leading to cell damage and ultimately apoptosis. It is noteworthy that commercially-used anticancer drugs, such as docetaxel, doxorubicin, cisplatin or etoposide, are also known to arrest the cycle of cancer cells in the G2/M phase [32][33][34]. Our findings correspond closely with those of previous reports on the cell cycle distribution in HL-60 cells following treatment with cisplatin.…”

Section: Discussionsupporting

confidence: 91%

Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues

et al. 2020

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A series of 3-benzylidenechrmanones 1, 3, 5, 7, 9 and their spiropyrazoline analogues 2, 4, 6, 8, 10 were synthesized. X-ray analysis confirms that compounds 2 and 8 crystallize in a monoclinic system in P21/n space groups with one and three molecules in each asymmetric unit. The crystal lattice of the analyzed compounds is enhanced by hydrogen bonds. The primary aim of the study was to evaluate the anti-proliferative potential of 3-benzylidenechromanones and their spiropyrazoline analogues towards four cancer cell lines. Our results indicate that parent compounds 1 and 9 with a phenyl ring at C2 have lower cytotoxic activity against cancer cell lines than their spiropyrazolines analogues. Analysis of IC50 values showed that the compounds 3 and 7 exhibited higher cytotoxic activity against cancer cells, being more active than the reference compound (4-chromanone or quercetin). The results of this study indicate that the incorporation of a pyrazoline ring into the 3-arylideneflavanone results in an improvement of the compounds’ activity and therefore it may be of use in the search of new anticancer agents. Further analysis allowed us to demonstrate the compounds to have a strong inhibitory effect on the cell cycle. For instance, compounds 2, 10 induced 60% of HL-60 cells to be arrested in G2/M phase. Using a DNA-cleavage protection assay we also demonstrated that tested compounds interact with DNA. All compounds at the concentrations corresponding to cytotoxic properties are not toxic towards red blood cells, and do not contribute to hemolysis of RBCs.

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Section: Discussionsupporting

confidence: 91%

Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues

et al. 2020

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“…Nonetheless, it is effective in only a subset of patients, highlighting the urgent clinical need of searching new therapeutic approaches for a larger number of OC patients.While the first generation of antimitotic drugs aimed at blocking cell division (classical antimicrotubule agents), the new generation is exploiting novel cancer-specific vulnerabilities such as the generated chromosomal instability (CIN) [19]. CIN-inducing cancer therapies target mitotic-specific alterations such as centrosome amplification or overexpressed checkpoint regulators to adversely impact in chromosome segregation, triggering cell death and thus trying to maximize clinical results [20,21]. Some of them, focused on the G2/M DNA damage checkpoint (e.g., PLK1, WEE1 G2 checkpoint kinase (WEE1) or telangiectasia mutated kinase (ATM)) are being investigated clinically in many cancers with promising results [22][23][24].…”

mentioning

confidence: 99%

Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer

Parrilla

Barber

Majem

et al. 2020

Cancers

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Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that Aurora Borealis (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA displayed synergistic effect in ovarian cancer models, offering promising therapeutic value. Altogether, our findings uncovered for the first time a critical role of BORA in the viability of human cancer cells providing potential novel therapeutic opportunities for ovarian cancer management.Cancers 2020, 12, 886 2 of 25 in cell cycle division. Nevertheless, even though BORA depletion has been reported to reduce the activity of PLK1 kinase, our understanding of its relevance in cancer is still very limited and there is no comprehensive study that defines the downstream biological consequences of BORA modulation in cancer. Recent evidence has shown that BORA is overexpressed in various tumors such breast, lung, and gastric adenocarcinomas and might serve as a prognostic biomarker [8].Ovarian cancer (OC), the most lethal gynecologic malignancy, is frequently diagnosed at advanced stages with disseminated disease, which limits the therapeutic options [9]. Despite improved cytoreductive surgical approaches and chemotherapy-based regimens, the survival of OC patients has remained largely unchanged during the last two decades [10,11]. Recent advances in cancer genomics have revealed that OC is molecularly a very heterogeneous disease, with extensive genomic instability, copy-number variations and defects in the homologous recombination repair pathway [12]. These genomic aberrations contribute to the development of tumor resistance, hampering effective treatment and ultimately causing disease recurrence [13], but also offer novel potential actionable vulnerabilities that can enhance the effectiveness of existing therapies.Molecular targeted therapies have been implemented routinely into the clinics changing OC management with the inclusion of anti-angiogenic compounds (i.e., monoclonal antibodies such Bevacizumab) [14,15] and poly ADP-ribose polymerases (PARP) inhibitors (i.e., Olaparib or Rucaparib) for breast-cancer (BRCA)-mutated carriers and BRCAness phenotype patients [16,17]. Synthetic lethality produced by PARP inhibitors enhances the therapeutic window after chemotherapy in recurrent platinum-sensitive OC subjects [18]. Nonetheless, it is effective in only a subset of patients, highlighting the urgent clinical need of searching...

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“…Detection of a damage that were activated in normal hemotopoesis cells, the Ataxia-Telangiectasia Mutated (ATM) played a central role in the activation of the G1/S cell cycle checkpoint, preventing cells with damaged DNA from starting the S phase. 16 There was an abnormality in activity of ALL checkpoint. The gene abnormality that caused expression of cyclins and Cyclin-Dependent Kinases (CDKs) disrupted so it could make a loss of cell cycle checkpoint control.…”

Section: Resultsmentioning

confidence: 99%

Correlation Percentage of S and G2/M With Percentage of Lymphoblasts in Pediatric Acute Lymphoblastic Leukemia

Armayani¹,

Hernaningsih²,

Retnowati³

et al. 2018

Indonesian J. Clin. Pathol. Med. Lab.

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Leukemia Limfoblastik Akut (ALL) merupakan keganasan klonal di sumsum tulang/Bone Marrow (BM). Angka bertahan hidup5 tahun saat ini >85%, tetapi 15-20% relaps sehingga perjalanan penyakit jelek. Perjalan penyakit jelek jika setelah tahap induksilimfoblas menetap di Darah Tepi (DT) dan BM >5% serta tahap S BM >6%. Tahap G2/M merupakan petunjuk prognosis ALL anak,selain itu sebagai target pengobatan. Tujuan penelitian menganalisis kenasaban persentase tahap S dan G2/M dengan persentaselimfoblas DT pasien ALL anak sebelum dan sesudah kemoterapi induksi. Jenis penelitian analitik observasional longitudinal (kohor)di ALL anak kasus baru diperiksa sebelum dan sesudah induksi. Persentase limfoblas secara mikroskopis. Persentase fase S dan G2/MflowcytometryBD Facs Callibur. Kenasaban bermakna hanya persentase tahap S dan limfoblas sebelum induksi (r=0,449; p=0,007).Kelainan gen ALL pada ekspresi cyclins dan CDK sehingga hilang kendali checkpoint siklus sel, merangsang transisi tahap G1 menjaditahap S. Persentase tahap S tidak berbeda pada remisi dan meninggal (p=0,138). Persentase tahap G2/M berbeda antara remisi danmeninggal (p=0,006) dan bernasab dengan luaran kemoterapi induksi (koefisien Eta= 0,744), G2/M ≥1,26% meramalkan remisi.Terdapat kenasaban antara persentase siklus sel tahap S dengan persentase limfobas sebelum kemoterapi induksi. Persentase siklus seltahap S memberikan gambaran siklus sel pada sel limfoblas. Terdapat kenasaban antara persentase siklus sel tahap G2/M dengan luarankemoterapi induksi tahap G2/M menjadi faktor peramal luaran kemoterapi induksi ALL. Perlu penelitian lanjutan dengan sampel BM,subtipe dan pengamatan semua tahap kemoterapi.

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The cell cycle checkpoint inhibitors in the treatment of leukemias

Cited by 59 publications

References 122 publications

Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues

Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues

Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer

Correlation Percentage of S and G2/M With Percentage of Lymphoblasts in Pediatric Acute Lymphoblastic Leukemia

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