Targeted methylation facilitates DNA double strand breaks and enhances cancer suppression: A DNA intercalating/methylating dual-action chimera Amonafidazene

Walunj, Dipak; Thankarajan, Ebaston; Prasad, Chandrashekhar; Baldan, Simone; Sherman, Michael Y.; Patsenker, L. D.; Gellerman, Gary

doi:10.1016/j.ejmech.2021.113811

Cited by 12 publications

(4 citation statements)

References 29 publications

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“…Among all tested compounds, 1, 7, and 11 exhibited the highest activity (IC 50 ≈ 3 μM) toward A549. The anticancer activity can be fine-tuned by changing both the 3-position of the naphthalimide ring and the side chain, in the order of −NO 2 (1) ≈ pyridine (11) and a tertiary nitrogen atom (7) ≈ secondary nitrogen (11) > primary nitrogen (12). Compounds 1 and 7 significantly caused DNA damage.…”

Section: T H Imentioning

confidence: 99%

“…9,10 DNA methylation has also been reported to promote DNA DSB S , and the DNA DSB S marker γH2AX is positively correlated with DNA methylation. 11,12 FTO is a DNA/RNA demethylase that can act as an oncogenic factor to trigger the progression of several human cancers, such as leukemia, glioblastoma, and so on. 13,14 FTO has been suggested as a promising target for drug development and cancer therapy.…”

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confidence: 99%

“…In the field of anticancer research, the development of chemotherapy products continues to receive great attention . It has been shown that 1,8-naphthalimides possess high antitumor activity against various human and murine cells. , Naphthalimides are conveniently synthesized from the corresponding 1,8-naphthalic anhydrides by reaction with an amine (R 2 NH 2 ) and the naphthalimide ring can be substituted with amino or nitro groups at the 3- or 4-position (Figure S1 in the Supporting Information), which allows the production of a large number of derivatives. − One of the important features of naphthalimides is their ability to target biological macromolecules, especially nucleic acids. , The planar nature of the aromatic core suggests that the molecule should intercalate itself between base pairs of DNA to induce DNA double-strand breaks (DSB S ), a behavior that has been assumed in many cases. , DNA methylation has also been reported to promote DNA DSB S , and the DNA DSB S marker γH2AX is positively correlated with DNA methylation. , FTO is a DNA/RNA demethylase that can act as an oncogenic factor to trigger the progression of several human cancers, such as leukemia, glioblastoma, and so on. , FTO has been suggested as a promising target for drug development and cancer therapy . Therefore, small-molecule inhibitors of FTO such as rhein, MO-I-500, meclofenamic acid (MA), fluorescein, entacapone, FB23, and Dac51, have been reported to inhibit the demethylation activities of FTO (Table S1) in the Supporting Information.…”

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confidence: 99%

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Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors

Ge,

Liu,

Wang

et al. 2023

ACS Med. Chem. Lett.

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Functional 1,8-naphthalimide derivatives are rapidly developing in the field of anticancer research. Herein, we designed and synthesized a series of naphthalimide derivatives with different substituents. Interestingly, 1,8-naphthalimide derivatives 1 and 7 inhibited a human demethylase FTO (the fat mass and obesityassociated protein). Computer simulation studies further indicated that 1 and 7 entered the FTO's structural domain II binding pocket through hydrophobic and hydrogen bonding interactions. Anticancer mechanism studies showed that 1 and 7 induced DNA damage and autophagic cell death in A549 cells. The high antiproliferative activity of 1 and 7 was further confirmed by 3D multicellular A549 tumor spheroid assays. This study focuses on the cytotoxicity and mode of action of naphthalimide derivatives, which not only have potential anticancer activity but also are potent demethylase inhibitors.

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Section: T H Imentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors

Ge,

Liu,

Wang

et al. 2023

ACS Med. Chem. Lett.

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“…Amonafide, a DNA intercalating agent, exhibits significant anticancer activities by interfering with topoisomerase 2 (Topo II) activity [1]. In recent years, many researchers have studied the chemotherapeutic effect of amonafide on tumors of various types, including melanoma, breast cancer, and hepatic carcinoma [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Amonafide Induces HUVEC Senescence by Inhibiting Autophagy

Xia¹,

Yu²,

He³

et al. 2023

Discovery Medicine

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Background: Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side effects are closely related to cellular senescence accumulation. Our study aims to examine whether amonafide causes senescence in human umbilical vein endothelial cell (HUVEC) lines and investigate its mechanisms associated with senescence. Methods: The experiments of expression of genes and proteins associated with aging were carried out with HUVEC cell lines. The experiments were divided into a control group and an amonafide group with different days. The HUVEC senescence cells were detected by SA-β-Gal staining, Western blotting detected the protein levels of p16, p53, AMPK (Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase), mTOR (mechanistic Target of Rapamycin), p62, and LC3 (microtubule-associated protein1 light chain 3, MAP1LC3). Fluorescence detected the expression of mRFP (monomeric Red Fluorescent Protein)-GFP (Green Fluorescent Protein)-LC3 and LC3 puncta of HUVEC cells. RT-qPCR (Real-Time Quantitative Polymerase Chain Reaction) tested the expressions of p53, p21, IL (Interleukin)-1β, IL-6 (Interleukin-6), IL-8 (Interleukin-8), and MCP-1 (Monocyte Chemoattractant Protein-1). CCK-8 (Cell Counting Kit-8) assessed the HUVEC cell viability. Results: Here, we reported that amonafide resulted in an increased proportion of SA-β-Gal positive cells, high expression of aging-related proteins (p53 p < 0.05; p16 p < 0.05), and aging-related genes (p53 p < 0.05; p21 p < 0.05; IL-1β p < 0.05; IL-6 p < 0.05; IL-8 p < 0.05; MCP-1 p < 0.05) on the 3rd day. Mechanistically, amonafide could cause an increase in the levels of the mTOR (p < 0.05) on days 1 and 3, and p62 protein (p < 0.05) on day 1, and a decline in LC3II (microtubule-associated protein1 light chain 3Ⅱ)/LC3I levels (p < 0.05) on day 3, which is associated with the regulation of senescence. Additionally, the viability of HUVECs (human umbilical vein endothelial cells) was significantly inhibited by amonafide starting with a concentration of 0.8 µm (p < 0.05). Conclusions: We first discovered that amonafide caused normal cellular senescence in our experiments. Amonafide-induced cellular aging by inhibiting autophagy and activating the mTOR pathway. The findings may offer new strategies for managing adverse reactions to amonafide.

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Antineoplastic effect of doxorubizen in vitro in continuous and primary human anaplastic thyroid cancer cells

Elia,

Ferrari,

Tkachenko

et al. 2024

Endocrine

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Targeted methylation facilitates DNA double strand breaks and enhances cancer suppression: A DNA intercalating/methylating dual-action chimera Amonafidazene

Cited by 12 publications

References 29 publications

Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors

Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors

Amonafide Induces HUVEC Senescence by Inhibiting Autophagy

Antineoplastic effect of doxorubizen in vitro in continuous and primary human anaplastic thyroid cancer cells

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