Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Khusnutdinova, É. F.; Petrova, А. V.; Zileeva, Zulfia R.; Kuzmina, U. Sh.; Зайнуллина, Л. Ф.; Vakhitova, Yu. V.; Babkov, Denis A.; Казакова, О. Б.

doi:10.3390/ijms22189796

Cited by 15 publications

(11 citation statements)

References 67 publications

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“…Our data showed significant increase of phosphorylated (active) form of ATM, p53, SMC1 and H2AX in both cell lines, implying that studied chalcone blocks cell cycle at G2/M phase via activation of ATM pathway. Furthermore, it has been proved that antiproliferative effect of several chalcones is associated with reactive oxygen species (ROS) generation [ 71 , 72 , 73 , 74 ]. Our results showed increased levels of 8-oxo-7,8-dihydroguanine, a marker of oxidative DNA damage, in ZK-CH-11d-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model

et al. 2022

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Although new chemotherapy significantly increased the survival of breast cancer (BC) patients, the use of these drugs is often associated with serious toxicity. The discovery of novel anticancer agents for BC therapy is expected. This study was conducted to explore the antiproliferative effect of newly synthesized indole chalcone derivative ZK-CH-11d on human BC cell lines. MTT screening, flow cytometry, Western blot, and fluorescence microscopy were used to evaluate the mode of cell death. ZK-CH-11d significantly suppressed the proliferation of BC cells with minimal effect against non-cancer cells. This effect was associated with cell cycle arrest at the G2/M phase and apoptosis induction. Apoptosis was associated with cytochrome c release, increased activity of caspase 3 and caspase 7, PARP cleavage, reduced mitochondrial membrane potential, and activation of the DNA damage response system. Furthermore, our study demonstrated that ZK-CH-11d increased the AMPK phosphorylation with simultaneous inhibition of the PI3K/Akt/mTOR pathway indicating autophagy initiation. However, chloroquine, an autophagy inhibitor, significantly potentiated the cytotoxic effect of ZK-CH-11d in MDA-MB-231 cells indicating that autophagy is not principally involved in the antiproliferative effect of ZK-CH-11d. Taking together the results from our experiments, we assume that autophagy was activated as a defense mechanism in treated cells trying to escape from chalcone-induced harmful effects.

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Section: Discussionmentioning

confidence: 99%

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model

et al. 2022

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“…Soloxolone methyl was prepared according to a previously reported method [ 28 ]. N , N ′-Carbonyldiimidazole (CDI), N , N -Dimethylethylenediamine (99%), N , N -dimethyl-1,3-propanediamine and tryptamine (98%) and 3-aminopyridine (99%) were purchased from ACROS organics.…”

Section: Methodsmentioning

confidence: 99%

“…There are many examples that the modification of triterpene compounds, including bardoxolone, with various amines leads to semisynthetic derivatives with improved properties compared to the starting materials [ 25 , 26 , 27 , 28 ]. Recently, Huang et al synthesized a series of cytotoxic ursolic acid amides by reacting the carboxyl group at the C-28 position with various amines, among which the compound functionalized by N 1 , N 1 -dimethylethane-1,2-diamine moiety was found to be the most potent due to enhanced cytotoxicity in a panel of malignant cells, its ability to trigger apoptosis and cell cycle arrest as well as to inhibit NF-κB signaling in human NCI-H460 lung cancer cells [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

et al. 2022

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The modification of natural or semisynthetic triterpenoids with amines can be explored as a promising strategy for improving their pharmacological properties. Here, we report the design and synthesis of 11 novel amide derivatives of soloxolone methyl (SM), a cyano enone-bearing derivative of 18βH-glycyrrhetinic acid. Analysis of their bioactivities in vitro and in silico revealed their high toxicity against a panel of tumor cells (average IC50(24 h) = 3.7 µM) and showed that the formation of amide moieties at the C-30 position of soloxolone did not enhance the cytotoxicity of derivatives toward tumor cells compared to SM, though it can impart an ability to pass across the blood–brain barrier. Further HPLC–MS/MS and mechanistic studies verified significant brain accumulation of hit compound 12 (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that 12 induced ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis and effectively blocked their clonogenicity, motility and capacity to form vessel-like structures. Further in vivo study demonstrated that intraperitoneal injection of 12 at a dosage of 20 mg/kg effectively inhibited the growth of U87 glioblastoma in a mouse xenograft model, reducing the proliferative potential of the tumor and leading to a depletion of collagen content and normalization of blood vessels in tumor tissue. The obtained results clearly demonstrate that 12 can be considered as a promising leading compound for drug development in glioblastoma treatment.

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“…Since multiple chalcone derivatives have an influence on the oxidative status in different experimental models of cancer (Wang et al 2020;Huang et al 2020;Guan et al 2021;Khusnutdinova et al 2021), we assessed the oxidative stress level in tumor tissue by measuring TAC upon CHE treatment. TAC in the ESC + Vehicle group was significantly increased (P < 0.05) in comparison with the negative control group.…”

Section: Che Induces Oxidative Stress and Dna Damage In Tumor Tissuesmentioning

confidence: 99%

[1,2,4] Triazolo [3,4-a]isoquinoline chalcone derivative exhibits anticancer activity via induction of oxidative stress, DNA damage, and apoptosis in Ehrlich solid carcinoma-bearing mice

WalyEldeen

El-Shorbagy

Hassaneen

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Despite the advances made in cancer therapeutics, their adverse effects remain a major concern, putting safer therapeutic options in high demand. Since chalcones, a group of flavonoids and isoflavonoids, act as promising anticancer agents, we aimed to evaluate the in vivo anticancer activity of a synthetic isoquinoline chalcone (CHE) in a mice model with Ehrlich solid carcinoma. Our in vivo pilot experiments revealed that the maximum tolerated body weight-adjusted CHE dose was 428 mg/kg. Female BALB/c mice were inoculated with Ehrlich ascites carcinoma cells and randomly assigned to three different CHE doses administered intraperitoneally (IP; 107, 214, and 321 mg/kg) twice a week for two consecutive weeks. A group injected with doxorubicin (DOX; 4 mg/kg IP) was used as a positive control. We found that in CHE-treated groups: (1) tumor weight was significantly decreased; (2) the total antioxidant concentration was substantially depleted in tumor tissues, resulting in elevated oxidative stress and DNA damage evidenced through DNA fragmentation and comet assays; (3) pro-apoptotic genes p53 and Bax, assessed via qPCR, were significantly upregulated. Interestingly, CHE treatment reduced immunohistochemical staining of the proliferative marker ki67, whereas BAX was increased. Notably, histopathological examination indicated that unlike DOX, CHE treatment had minimal toxicity on the liver and kidney. In conclusion, CHE exerts antitumor activity via induction of oxidative stress and DNA damage that lead to apoptosis, making CHE a promising candidate for solid tumor therapy.

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Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Cited by 15 publications

References 67 publications

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

[1,2,4] Triazolo [3,4-a]isoquinoline chalcone derivative exhibits anticancer activity via induction of oxidative stress, DNA damage, and apoptosis in Ehrlich solid carcinoma-bearing mice

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