Natural products hybrids: 3,5,4′-Trimethoxystilbene-5,6,7-trimethoxyflavone chimeric analogs as potential cytotoxic agents against diverse human cancer cells

Hassan, Ahmed H.E.; Choi, Eunwoo; Yoon, Yoon Mi; Lee, Kun Won; Yoo, Sung Yeun; Cho, Min Chang; Yang, Jae-Seung; Kim, Hye In; Hong, Jongki; Shin, Ji‐Sun; Chung, Kyung‐Sook; Lee, Jeonghun; Lee, Kyung‐Tae; Lee, Yong Sup

doi:10.1016/j.ejmech.2018.10.062

Cited by 47 publications

(32 citation statements)

References 56 publications

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“…Clinically, anticancer drugs for the treatment of breast cancer have many adverse reactions. 24 Thus, it is important and necessary to research and develop a new anticancer drug that is highly effective and of low toxicity. In recent years, tumor epidemiology research has found that the isolation of effective anti-cancer active ingredients from plants has attracted more and more attention from scholars and is a hot spot for cancer prevention and treatment.…”

Section: Discussionmentioning

confidence: 99%

Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway

Zhou¹,

Wu²,

Qin³

et al. 2020

DDDT

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Background: 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) has been reported to inhibit a variety of cancer cell lines. The purpose of this study was to investigate the effects of DMDD on 4T1 breast cancer cells and the effects of DMDD on 4T1 breast cancer in mice and its molecular mechanisms. Methods: 4T1 breast cancer cells were treated with different concentrations of DMDD, and their proliferation, apoptosis, cell-cycle distribution, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT, Acridine orange and ethidium bromide dual staining analysis (AO/EB) dual staining, flow cytometry, scratch test, and the Transwell assay. Relative quantitative real-time qPCR analysis and Western blot were applied to examine the expression levels of related genes and proteins. In animal experiments, we established a xenograft model to assess the anti-breast cancer effects of DMDD by evaluating the inhibition rate. The apoptotic activity of DMDD was evaluated by hematoxylin-eosin (HE) staining, transmission electron microscope (TEM) analysis and TdT-mediated dUTP nick end labeling (TUNEL) assays. The mRNA expression levels of MAPK pathway components were detected by relative quantitative real-time qPCR. In addition, the protein expression levels of MAPK pathway components were assessed through immunohistochemical assays and Western blotting. Results: Experiments showed that DMDD could inhibit the proliferation, migration, invasion of 4T1 cells and induce cellular apoptosis and G1 cell cycle arrest. Moreover, DMDD down-regulated the mRNA expressions of raf1, mek1, mek2, erk1, erk2, bcl2, and upregulated the mRNA expression of bax. DMDD reduced the protein expressions of p-raf1, p-mek, perk , p-p38, Bcl2, MMP2, MMP9 and increased the protein expressions of Bax and p-JNK. The results showed that DMDD can effectively reduce the tumor volume and weight of breast cancer in vivo, up-regulate the expression of IL-2, down-regulate the expression of IL-4 and IL-10, induce the apoptosis of breast cancer cells in mice, and regulate the expression of genes and proteins of the MAPK pathway. Conclusion: Our study indicates that DMDD can inhibit proliferation, migration, and invasion and induces apoptosis and cell-cycle arrest of 4T1 breast cancer cells. Also, our findings indicate that DMDD induces the apoptosis of breast cancer cells and inhibits the growth in mice. Its mechanism may be related to the MAPK pathway.

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Section: Discussionmentioning

confidence: 99%

Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway

Zhou¹,

Wu²,

Qin³

et al. 2020

DDDT

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“…Cancer remains a major global health problem. All available anticancer agents currently have disadvantages such as resistance and side effects 14. Therefore, it is necessary to introduce a new anticancer agent.…”

Section: Discussionmentioning

confidence: 99%

Dicerandrol B: a natural xanthone dimer induces apoptosis in cervical cancer HeLa cells through the endoplasmic reticulum stress and mitochondrial damage

Gao¹,

Guo²,

Wang³

et al. 2019

OTT

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Background: Dicerandrol B is a natural antitumor agent that can be isolated from the endophytic fungus, Phomopsis sp. The present study investigated the effects of dicerandrol B on human cervical cancer HeLa cells. Materials and methods: In this study, dicerandrol B was identified by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. We used MTT to detect the cell viability. Flow cytometry was used to analyze the apoptosis and cell cycle. Western blot was used to examine the expression of related proteins. Results: Dicerandrol B was isolated from the endophytic fungus Phomopsis sp. The MTT assay and flow cytometry showed that dicerandrol B significantly inhibited HeLa cell viability and induced G2/M cell cycle arrest. Western blot analysis demonstrated that dicerandrol B increased the levels of GRP78, ubiquitin, cleaved PARP, and Bax protein, decreased the levels of PARP and Bcl-2 protein, and caused an increase in the Bax/Bcl-2 ratio in HeLa cells. Dicerandrol B increased the production of ROS in HeLa cells, which was attenuated by the antioxidant N-acetyl-l-cysteine. Conclusion: These findings suggest that dicerandrol B induces apoptosis in human HeLa cells, possibly through the endoplasmic reticulum stress and mitochondrial apoptotic pathways. This suggests that dicerandrol B possesses strong anticancer activity in cervical cancer and provides insight into the underlying mechanisms.

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“…By adopting this strategy, we recently reported the synthesis of natural product hybrids that could induce potential anti-proliferative activity [16]. We hybridized 3,5,4 -trimethoxystilbene (TMS), which is a permethylated analog of resveratrol, with 5,6,7-trimethoxyflavone (TMF), which is a flavone derivative whose anti-cancer activity is triggered by nuclear factor-kappa B (NF-кB) suppression [17][18][19]. It is well known that resveratrol has been the subject of several biological evaluations, as well as clinical trials as a potential anticancer agent impacting several pathways that control the proliferation and survival of cells [19].…”

Section: Introductionmentioning

confidence: 99%

“…We hybridized 3,5,4 -trimethoxystilbene (TMS), which is a permethylated analog of resveratrol, with 5,6,7-trimethoxyflavone (TMF), which is a flavone derivative whose anti-cancer activity is triggered by nuclear factor-kappa B (NF-кB) suppression [17][18][19]. It is well known that resveratrol has been the subject of several biological evaluations, as well as clinical trials as a potential anticancer agent impacting several pathways that control the proliferation and survival of cells [19]. Nevertheless, the clinical benefit of resveratrol is not sufficiently confirmed and it has poor pharmacokinetics, as well as chemical instabilities that hinder further development [20,21].…”

Section: Introductionmentioning

confidence: 99%

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The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

Hong

Chung

Shin

et al. 2019

Cancers

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We previously reported the potential anti-proliferative activity of 3-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-N-(3,4,5-trimethoxyphenyl) benzamide (TMS-TMF-4f) against human cancer cells; however, the underlying molecular mechanisms have not been investigated. In the present study, TMS-TMF-4f showed the highest cytotoxicity in human cervical cancer cells (HeLa and CaSki) and low cytotoxicity in normal ovarian epithelial cells. Annexin V-FITC and propidium iodide (PI) double staining revealed that TMS-TMF-4f-induced cytotoxicity was caused by the induction of apoptosis in both HeLa and CaSki cervical cancer cells. The compound TMS-TMF-4f enhanced the activation of caspase-3, caspase-8, and caspase-9 and regulated Bcl-2 family proteins, which led to mitochondrial membrane potential (MMP) loss and resulted in the release of cytochrome c and Smac/DIABLO into the cytosol. Also, TMS-TMF-4f suppressed both constitutive and IL-6-inducible levels of phosphorylated STAT3 (p-STAT3) and associated proteins such as Mcl-1, cyclin D1, survivin, and c-Myc in both cervical cancer cells. STAT-3 overexpression completely ameliorated TMS-TMF-4f-induced apoptotic cell death and PARP cleavage. Docking analysis revealed that TMS-TMF-4f could bind to unphosphorylated STAT3 and inhibit its interconversion to the activated form. Notably, intraperitoneal administration of TMS-TMF-4f (5, 10, or 20 mg/kg) decreased tumor growth in a xenograft cervical cancer mouse model, demonstrated by the increase in TUNEL staining and PARP cleavage and the reduction in p-STAT3, Mcl-1, cyclin D1, survivin, and c-Myc expression levels in tumor tissues. Taken together, our results suggest that TMS-TMF-4f may potentially inhibit human cervical tumor growth through the induction of apoptosis via STAT3 suppression.

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Natural products hybrids: 3,5,4′-Trimethoxystilbene-5,6,7-trimethoxyflavone chimeric analogs as potential cytotoxic agents against diverse human cancer cells

Cited by 47 publications

References 56 publications

<p>Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway</p>

<p>Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway</p>

<p>Dicerandrol B: a natural xanthone dimer induces apoptosis in cervical cancer HeLa cells through the endoplasmic reticulum stress and mitochondrial damage</p>

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

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