598 POSTER Voreloxin (formerly SNS-595) is a potent DNA intercalator and topoisomerase II poison that induces cell cycle dependent DNA damage and rapid apoptosis in cancer cell lines

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

Download Full-text

Anticancer Properties of a New Hybrid Analog AD-013 Combining a Coumarin Scaffold with an α-methylene-δ-lactone Motif

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170921123654 ◽

2018 ◽

Vol 18 (3) ◽

pp. 450-457 ◽

Cited By ~ 3

Author(s):

Angelika Dlugosz ◽

Katarzyna Gach-Janczak ◽

Jacek Szymanski ◽

Dariusz Deredas ◽

Henryk Krawczyk ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Pcr Analysis ◽

Cytotoxic Activities ◽

Anticancer Properties ◽

Apoptotic Genes ◽

Mcf 7

Background: Coumarin is a natural phytochemical but as such has no medical uses. However, various natural and synthetic coumarin analogs attract attention due to their interesting biological properties. Objective: Here, we evaluated and compared anticancer properties of a new synthetic hybrid compound AD- 013, which integrates a coumarin moiety and an α-methylene-δ-lactone motif, with novobiocin, a natural antibiotic bearing a coumarin scaffold. Methods: Cytotoxic activities of compound AD-013 and novobiocin were assessed by the MTT assay. In order to explore the mechanism of anticancer activity of analog AD-013, we performed quantitative real-time PCR analysis of apoptosis- and cell cycle-related genes. The ability of AD-013 and novobiocin to induce apoptosis and DNA damage was studied by flow cytometry. Results: The cytotoxic activity of this new compound was compared with the activity of a coumarin-based antibiotic novobiocin against two cancer cell lines, MCF-7 and HL-60 and also against normal human cells, MCF- 10A and HUVEC. AD-013 was much more cytotoxic than novobiocin in both cancer cell lines and showed some selectivity against MCF-7 cancer cells as compared with MCF-10A healthy cells. Expression levels of the pro-apoptotic genes significantly increased while the anti-apoptotic genes, were down-regulated for both compounds in both cancer cell lines. </P><P> AD-013 was able to inhibit cell proliferation, generate DNA damage and induce apoptosis. The obtained data showed that this compound caused the cell cycle arrest in subG0/G1 in both cancer cell lines. Conclusion: The new hybrid analog was a much stronger apoptosis inducer than novobiocin and activated the intrinsic pathway of apoptosis.

Download Full-text

CELL CYCLE RESPONSES TO DNA DAMAGE IN P53 WT CANCER CELL LINES

Biology of the Cell ◽

10.1016/s0248-4900(97)86889-x ◽

1996 ◽

Vol 88 (1-2) ◽

pp. 81-81 ◽

Cited By ~ 1

Author(s):

Magali OLIVIER ◽

Charles THEILLET

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines

Download Full-text

RAD51B Activity and Cell Cycle Regulation in Response to DNA Damage in Breast Cancer Cell Lines

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s17766 ◽

2014 ◽

Vol 8 ◽

pp. BCBCR.S17766 ◽

Cited By ~ 2

Author(s):

Phoebe S. Lee ◽

Jun Fang ◽

Lea Jessop ◽

Timothy Myers ◽

Preethi Raj ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Dna Damage ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Cell Cycle Checkpoint ◽

Breast Cancer Cell Lines ◽

Cycle Checkpoint

Common genetic variants mapping to two distinct regions of RADS1B, a paralog of RADS1, have been associated with breast cancer risk in genome-wide association studies (GWAS). RADS1B is a plausible candidate gene because of its established role in the homologous recombination (HR) process. How germline genetic variation in RADS1B confers susceptibility to breast cancer is not well understood. Here, we investigate the molecular function of RADS1B in breast cancer cell lines by knocking down RADS1B expression by small interfering RNA and treating cells with DNA-damaging agents, namely cisplatin, hydroxyurea, or methyl-methanesulfonate. Our results show that RAD51B-depleted breast cancer cells have increased sensitivity to DNA damage, reduced efficiency of HR, and altered cell cycle checkpoint responses. The influence of RAD51B on the cell cycle checkpoint is independent of its role in HR and further studies are required to determine whether these functions can explain the RADS1B breast cancer susceptibility alleles.

Download Full-text

Influence of AUF1 targeting siRNA on cell cycle-related proteins in thyroid cancer cell lines

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2006-932951 ◽

2006 ◽

Vol 114 (S 1) ◽

Author(s):

B Trojanowicz ◽

Z Chen ◽

J Bialek ◽

Y Radestock ◽

S Hombach-Klonisch ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Thyroid Cancer Cell ◽

Thyroid Cancer Cell Lines ◽

Related Proteins

Download Full-text

Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence

Cells ◽

10.3390/cells10030610 ◽

2021 ◽

Vol 10 (3) ◽

pp. 610

Author(s):

Apostolos Menegakis ◽

Rob Klompmaker ◽

Claire Vennin ◽

Aina Arbusà ◽

Maartje Damen ◽

...

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cancer Cell ◽

Radiation Treatment ◽

Large Fraction ◽

Radiation Sensitivity ◽

Cancer Cell Lines ◽

Cycle Phase ◽

Multicellular Spheroids ◽

Phase Duration

Double strand breaks (DSBs) are highly toxic to a cell, a property that is exploited in radiation therapy. A critical component for the damage induction is cellular oxygen, making hypoxic tumor areas refractory to the efficacy of radiation treatment. During a fractionated radiation regimen, these hypoxic areas can be re-oxygenated. Nonetheless, hypoxia still constitutes a negative prognostic factor for the patient’s outcome. We hypothesized that this might be attributed to specific hypoxia-induced cellular traits that are maintained upon reoxygenation. Here, we show that reoxygenation of hypoxic non-transformed RPE-1 cells fully restored induction of DSBs but the cells remain radioresistant as a consequence of hypoxia-induced quiescence. With the use of the cell cycle indicators (FUCCI), cell cycle-specific radiation sensitivity, the cell cycle phase duration with live cell imaging, and single cell tracing were assessed. We observed that RPE-1 cells experience a longer G1 phase under hypoxia and retain a large fraction of cells that are non-cycling. Expression of HPV oncoprotein E7 prevents hypoxia-induced quiescence and abolishes the radioprotective effect. In line with this, HPV-negative cancer cell lines retain radioresistance, while HPV-positive cancer cell lines are radiosensitized upon reoxygenation. Quiescence induction in hypoxia and its HPV-driven prevention was observed in 3D multicellular spheroids. Collectively, we identify a new hypoxia-dependent radioprotective phenotype due to hypoxia-induced quiescence that accounts for a global decrease in radiosensitivity that can be retained upon reoxygenation and is absent in cells expressing oncoprotein E7.

Download Full-text

A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition

Biochemical Journal ◽

10.1042/bj20080639 ◽

2008 ◽

Vol 415 (1) ◽

pp. 97-110 ◽

Cited By ~ 98

Author(s):

Neil E. Torbett ◽

Antonio Luna-Moran ◽

Zachary A. Knight ◽

Andrew Houk ◽

Mark Moasser ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Therapeutics ◽

Cancer Cell Lines ◽

Genetic Alterations ◽

Breast Cancer Cell Lines ◽

Selective Inhibitors

The PI3K (phosphoinositide 3-kinase) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small-molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we have demonstrated that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110α inhibitors were generally effective in inhibiting the phosphorylation of PKB (protein kinase B)/Akt and S6, two downstream components of PI3K signalling, in most cell lines examined. In contrast, p110β-selective inhibitors only reduced PKB/Akt phosphorylation in PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing cell-cycle arrest in the G1 phase, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell-cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signalling pathways. Taken together, our data indicate that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts.

Download Full-text