A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors

Inbar-Rozensal, Dana; Castiel, Asher; Visochek, Leonid; Castel, David; Dantzer, Françoise; Izraeli, Shai; Cohen-Armon, Malka

doi:10.1186/bcr2445

Cited by 52 publications

(76 citation statements)

References 41 publications

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“…Our previous results revealed cell death and de-clustered extra-centrosomes in several types of fixed multi-centrosomal cancer cells that were treated with PJ-34. In contrast, normal proliferating cells were not impaired 2,3 . Centrosomes were identified by double labeling with antibodies directed against centrine1 and γ-tubulin in the fixed extra-centrosomal cells 2 .…”

Section: Representative Resultsmentioning

confidence: 87%

“…Understanding this death mechanism will enable exclusive eradication of cancer cells while sparing healthy tissues 5,10 . Thus, compounds that activate mitotic catastrophe cell death offer a new mode of a selective cancer therapy, which may be efficient in a wide range of human solid cancers.Our results suggest that confocal imaging can be used to identify molecules affecting extra-centrosomes clustering in mitosis 2,3 , rendering these compounds cancer targeting drug candidates.…”

Section: Introductionmentioning

confidence: 99%

“…These cells were resistant to the cytotoxic activity of PJ-34. PJ-34 did not interfere with their cell cycle during 96 hr incubation or affect their centrosomes and bi-focal spindle formation 2,3 . Bipolar centrosome assembly is crucial for bipolar spindle formation in mitosis 4,5 .…”

Section: Introductionmentioning

confidence: 99%

“…However, recently we discovered that PJ-34, at twice higher concentration than that inducing PARP1 inhibition, can exclusively cause cell death in human cancer cells 2,3 . The more rapid the proliferation of the cell was, the more efficient the eradication of the cells was.…”

Section: Introductionmentioning

confidence: 99%

“…Many human cancer cells harbor multicentrosomes 4,5 . Incubation of human breast cancer cells MDA-MB-231, which harbor supernumerary centrosomes, with 20 μM PJ-34 efficiently eradicated these cells within 72-96 hr without impairing quiescent cells or some benign proliferating cells harboring two centrosomes in mitosis 2,3 . Benign cells included human mammary epithelial cells MCF-10, Human endothelial cells (huvec) and primary mesenchymal cells prepared from human thymus.…”

Section: Introductionmentioning

confidence: 99%

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Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

Castiel

Visochek

Mittelman

et al. 2013

JoVE

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Phenanthrene derivatives acting as potent PARP1 inhibitors prevented the bi-focal clustering of supernumerary centrosomes in multicentrosomal human cancer cells in mitosis. The phenanthridine PJ-34 was the most potent molecule. Declustering of extra-centrosomes causes mitotic failure and cell death in multi-centrosomal cells. Most solid human cancers have high occurrence of extra-centrosomes. The activity of PJ-34 was documented in real-time by confocal imaging of live human breast cancer MDA-MB-231 cells transfected with vectors encoding for fluorescent γ-tubulin, which is highly abundant in the centrosomes and for fluorescent histone H2b present in the chromosomes. Aberrant chromosomes arrangements and de-clustered γ-tubulin foci representing declustered centrosomes were detected in the transfected MDA-MB-231 cells after treatment with PJ-34. Un-clustered extra-centrosomes in the two spindle poles preceded their cell death. These results linked for the first time the recently detected exclusive cytotoxic activity of PJ-34 in human cancer cells with extra-centrosomes de-clustering in mitosis, and mitotic failure leading to cell death. According to previous findings observed by confocal imaging of fixed cells, PJ-34 exclusively eradicated cancer cells with multi-centrosomes without impairing normal cells undergoing mitosis with two centrosomes and bi-focal spindles. This cytotoxic activity of PJ-34 was not shared by other potent PARP1 inhibitors, and was observed in PARP1 deficient MEF harboring extracentrosomes, suggesting its independency of PARP1 inhibition. Live confocal imaging offered a useful tool for identifying new molecules eradicating cells during mitosis. Video LinkThe video component of this article can be found at

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Section: Representative Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

Castiel

Visochek

Mittelman

et al. 2013

JoVE

Self Cite

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Hydroxamic Acids as PARP‐1 Inhibitors: Molecular Design and Anticancer Activity of Novel Phenanthridinones

Bondar,

Bragina,

Lee

et al. 2023

Helvetica Chimica Acta

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Poly(ADP‐ribose)polymerase‐1 (PARP‐1) is a promising target for antitumor agents. This study presents the first evidence of hydroxamic acids as efficient PARP inhibitors. Molecular docking and molecular dynamics simulations revealed that N−O substituted phenanthridinones form a complex interplay with PARP‐1. A series of cyclic aryl hydroxamic acids, N‐(benzyloxy)‐ and N‐(hydroxy)phenanthridinones, were prepared through a ligand‐free methodology from N‐(benzyloxy)benzamides using dual C−H/N−H bond activation. Three of the computed hit compounds exhibited significant activity in cell‐based and enzymatic assays, inhibiting PARP‐1 in the low‐nanomolar range. The antiproliferative activity of all prepared compounds and the reference compounds PJ34 and Olaparib was evaluated in cancer cells (HepG2, BxPC3, MDA‐MD‐231, and HeLa) and in noncancer cell lines (NIH 3T3 and HEK 293). An N‐(benzyloxy)‐ and an N‐(hydroxy)phenanthridinone showed the most promising properties as leads for developing therapeutics with a submicromolar activity window. The study highlights the potential utility of this scaffold for PARP inhibitors and the importance of target‐specific design to minimize toxicity and side effects.

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Computational benchmarking of putative KIFC1 inhibitors

Sharma

Setiawan

Hamelberg

et al. 2022

Medicinal Research Reviews

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The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo‐bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell‐targeting weapon. The kinesin‐14 motor protein KIFC1 is a minus end‐directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever‐increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in‐depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first‐of‐kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision‐making in the selection and design of potent inhibitors.

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A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors

Cited by 52 publications

References 41 publications

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

Hydroxamic Acids as PARP‐1 Inhibitors: Molecular Design and Anticancer Activity of Novel Phenanthridinones

Computational benchmarking of putative KIFC1 inhibitors

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