Discovery of Natural Dimeric Naphthopyrones as Potential Cytotoxic Agents Through ROS-Mediated Apoptotic Pathway

A study on the secondary metabolites of Aspergillus sp. XNM-4, which was derived from marine algae Leathesia nana (Chordariaceae), led to the identification of one previously undescribed (1) and seventeen known compounds (2−18). Their planar structures were established by extensive spectroscopic analyses, while the stereochemical assignments were defined by electronic circular dichroism (ECD) calculations. The biological activities of the compounds were assessed on five human cancer cell lines (PANC-1, A549, MDA-MB-231, Caco-2, and SK-OV-3), and one human normal cell line (HL-7702) using an MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide] assay. Among them, the dimeric naphthopyrones 7, 10 and 12 exhibited potent cytotoxicity. Further mechanism studies showed that 12 induced apoptosis, arrested the cell cycle at the G0/G1 phase in the PANC-1 cells, caused morphological changes and generated ROS; and it induces PANC-1 cells apoptosis via ROS-mediated PI3K/Akt signaling pathway.

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Targeting apoptosis via inactivation of PI3K/Akt/mTOR signaling pathway involving NF-κB by geraniin in HT-29 human colorectal adenocarcinoma cells

Progress in Drug Discovery & Biomedical Science ◽

10.36877/pddbs.a0000030 ◽

2019 ◽

Vol 2 (1) ◽

Author(s):

Chim Kei Chan ◽

Liu Ying Tang ◽

Bey Hing Goh ◽

Habsah Abdul Kadir

Keyword(s):

Colorectal Adenocarcinoma ◽

Therapeutic Potential ◽

Human Cancer ◽

Morphological Changes ◽

Biological Activities ◽

Mtor Pathway ◽

Human Cancer Cell Lines ◽

Adenocarcinoma Cells ◽

Underlying Mechanisms ◽

Ht 29

Dietary phytochemicals possess a variety of biological activities which can be widely discovered in fruits, vegetables and herbs. Geraniin, an ellagitannin is commonly found in fruits and herbs which possesses multitude of health benefits including anti-diabetic, hepatoprotective, anti-inflammatory and anticancer. However, the effects of geraniin on human colorectal adenocarcinoma cells have yet to be evaluated. This study aimed to investigate the apoptotic effects of geraniin against selected human cancer cell lines and elucidate its underlying mechanisms. Geraniin exhibited the strongest cytotoxic effect on HT-29 cells as determined by MTT assay. Events of apoptosis induced by geraniin in HT-29 cells was portrayed by apoptotic morphological changes, externalization of phosphatidylserine, DNA fragmentation and dissipation of mitochondrial membrane potential. Western blot analysis was then used to investigate the mechanisms underlying observed growth inhibition. Geraniin was found to initiate p53 activation further resulting in elevation of Bak/Bcl-xL ratio and caspase-3 activation. This eventually led to HT-29 cell death via apoptosis. Additionally, exposure of geraniin on HT-29 cells found to suppress the PI3K/Akt/mTOR pathway and suppression of NF-kB. Cumulative evidences in this study suggests that geraniin inhibited colorectal adenocarcinoma cell proliferation via apoptosis induction and suppression of PI3K/Akt/mTOR pathway. Thus, these findings provide novel mechanistic insight for the therapeutic potential of geraniin in the treatment of colorectal adenocarcinoma.

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Evaluation of Pyrano[3,2 C] Quinoline Analogues as Anticancer Agents

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190308122734 ◽

2019 ◽

Vol 19 (10) ◽

pp. 1285-1292 ◽

Cited By ~ 2

Author(s):

Kuldip D. Upadhyay ◽

Anamik K. Shah

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

Biological Activities ◽

Cytotoxic Agents ◽

Tumor Growth Inhibition ◽

Mice Model ◽

One Pot ◽

Aryl Ring ◽

Hct 116

Background: Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents. Objective: The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity. Methods: A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model. Results: The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model. Conclusion: The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.

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High-risk HPV-positive human cancer cell lines show different sensitivity to cisplatin-induced apoptosis correlated with the p21Waf1/Cip1 level

Cancer Letters ◽

10.1016/s0304-3835(96)04362-5 ◽

1996 ◽

Vol 108 (1) ◽

pp. 15-23 ◽

Cited By ~ 13

Author(s):

Kohsei Funaoka ◽

Masanobu Shindoh ◽

Toshiharu Yamashita ◽

Kei Fujinaga ◽

Akira Amemiya ◽

...

Keyword(s):

High Risk ◽

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Induced Apoptosis ◽

High Risk Hpv

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Structurally Simple Phenanthridine Analogues Based on Nitidine and Their Antitumor Activities

Molecules ◽

10.3390/molecules24030437 ◽

2019 ◽

Vol 24 (3) ◽

pp. 437

Author(s):

Shu-Qin Qin ◽

Lian-Chun Li ◽

Jing-Ru Song ◽

Hai-Yun Li ◽

Dian-Peng Li

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

A549 Cells ◽

Anticancer Activities ◽

Human Cancer Cell Lines ◽

Ic50 Value ◽

Ic50 Values ◽

Diphenyl Tetrazolium Bromide ◽

Conjugated Compounds

A series of novel structurally simple analogues based on nitidine was designed and synthesized in search of potent anticancer agents. The antitumor activity against human cancer cell lines (HepG2, A549, NCI-H460, and CNE1) was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The results showed that some of them had good anticancer activities, especially derivatives with a [(dimethylamino)ethyl]amino side chain in the C-6 position. Planar conjugated compounds 15a, 15b, and 15c, with IC50 values of 1.20 μM, 1.87 μM, and 1.19 μM against CNE1 cells, respectively, were more active than nitidine chloride. Compound 15b and compound 15c with IC50 values of 1.19 μM and 1.37 μM against HepG2 cells and A549 cells demonstrated superior activities to nitidine. Besides, compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells, particularly against CNE1 cells with the IC50 value of 1.13 μM.

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The Design and Synthesis of Novel Phenothiazine Derivatives as Potential Cytotoxic Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180816666181115112236 ◽

2019 ◽

Vol 17 (1) ◽

pp. 57-67

Author(s):

Yepeng Luan ◽

Jinyi Liu ◽

Jianjun Gao ◽

Jinhua Wang

Keyword(s):

Cell Lines ◽

High Efficiency ◽

Human Cancer ◽

Human Tumor ◽

Cytotoxic Agents ◽

Cancer Drug ◽

Human Cancer Cell Lines ◽

Incidence And Mortality ◽

Anti Cancer

Background: Cancer incidence and mortality have been increasing and cancer is still the leading cause of death all over the world. Despite the enormous progress in cancer treatment, many patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for anti-cancer drug discovery. Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations against other 22 human tumor cell lines. Mechanism was also studied. Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and cell apoptosis by activating the caspase 3 activity. Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer drug development.

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13-Ethylberberine Induces Apoptosis through the Mitochondria-Related Apoptotic Pathway in Radiotherapy-Resistant Breast Cancer Cells

Molecules ◽

10.3390/molecules24132448 ◽

2019 ◽

Vol 24 (13) ◽

pp. 2448 ◽

Cited By ~ 9

Author(s):

Hana Jin ◽

Young Shin Ko ◽

Sang Won Park ◽

Ki Churl Chang ◽

Hye Jung Kim

Keyword(s):

Breast Cancer ◽

Human Cancer ◽

Biological Effects ◽

Bacterial Species ◽

Extrinsic Pathway ◽

Apoptotic Pathway ◽

Septic Mouse ◽

Human Cancer Cell Lines ◽

Apoptotic Genes ◽

Anti Inflammatory

Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated macrophage and septic mouse models. Thus, in this study, we aimed to examine the anticancer effects of 13-EBR and its mechanisms in radiotherapy-resistant (RT-R) MDA-MB-231 cells derived from the highly metastatic MDA-MB-231 cells. When we compared the gene expression between MDA-MB-231 and RT-R MDA-MB-231 cells with an RNA microarray, RT-R MDA-MB-231 showed higher levels of anti-apoptotic genes and lower levels of pro-apoptotic genes compared to MDA-MB-231 cells. Accordingly, we examined the effect of 13-EBR on the induction of apoptosis in RT-R MDA-MB-231 and MDA-MB-231 cells. The results showed that 13-EBR reduced the proliferation and colony-forming ability of both MDA-MB-231 and RT-R MDA-MB-231 cells. Moreover, 13-EBR induced apoptosis by promoting both intracellular and mitochondrial reactive oxygen species (ROS) and by regulating the apoptosis-related proteins involved in the intrinsic pathway, not in the extrinsic pathway. These results suggest that 13-EBR has pro-apoptotic effects in RT-R MDA-MB-231 and MDA-MB-231 cells by inducing mitochondrial ROS production and activating the mitochondrial apoptotic pathway, providing useful insights into new potential therapeutic strategies for RT-R breast cancer treatment.

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Biological Activity and Chemical Constituents of Essential Oil and Extracts of Murraya microphylla

Natural Product Communications ◽

10.1177/1934578x1501000935 ◽

2015 ◽

Vol 10 (9) ◽

pp. 1934578X1501000

Author(s):

Hai-Ning Lv ◽

Ke-Wu Zeng ◽

Bing-Yu Liu ◽

Yun Zhang ◽

Peng-Fei Tu ◽

...

Keyword(s):

Essential Oil ◽

Human Cancer ◽

Biological Activities ◽

Chemical Constituents ◽

Cytotoxic Activities ◽

Active Components ◽

Human Cancer Cell Lines ◽

Total Oil ◽

Promising Development ◽

Carbazole Alkaloids

Murraya microphylla is the most closely related species to M. koenigii (Curry tree). Inspired by the traditional effects of M. koenigii, the antioxidant, anti-inflammatory, and cytotoxic activities of the essential oil and extracts of M. microphylla were evaluated for the first time. The light petroleum and chloroform extracts were found to be able to scavenge DPPH free radicals, inhibit linoleic acid peroxidation, and nitric oxide production, as well as to present cytotoxicity to the human cancer cell lines HepG2, Bel7402, Bel7403, and Hela, but the essential oil only showed moderate activities. Chemical analysis of the active extracts by LC-DAD-MSn indicated that carbazole alkaloids were the main constituents. GC-MS analysis of the essential oil resulted in identification of 91 constituents, representing 96.9% of the total oil, with ( E)-caryophyllene (18.4%) and terpinen-4-ol (12.6%) as the major constituents. These results demonstrate that M. microphylla has similar biological activities, as well as chemical constituents to M. koenigii, and the carbazole alkaloids were disclosed to be the main potential active components. A promising development as a flavor and potential therapeutic agent could thus be predicated for this plant.

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A New Pentacyclic Ergosteroid from Fungus Aspergillus sp. SCSIO41211 Derived of Mangrove Sediment Sample

Natural Product Communications ◽

10.1177/1934578x1801301214 ◽

2018 ◽

Vol 13 (12) ◽

pp. 1934578X1801301 ◽

Cited By ~ 2

Author(s):

Huaming Tao ◽

Yunqiu Li ◽

Xiuping Lin ◽

Xuefeng Zhou ◽

Junde Dong ◽

...

Keyword(s):

Methyl Ester ◽

Antiviral Activity ◽

Ochratoxin A ◽

Ethyl Ester ◽

Sediment Sample ◽

Human Cancer ◽

Mangrove Sediment ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Aspergillus Sp

Chemical investigation of the fungus Aspergillus sp. SCSIO41211 derived of mangrove sediment sample afforded a ergostane-type pentacyclic steroid, (22 S, 23 R)-12α,14α,23α-trihydroxy-16,22-epoxy-ergosta-4,8-dien-3,11-dione (1), together with seven known compounds, flavacol (2), aspergilliamide (3), ochratoxin A methyl ester (4), ochratoxin A ethyl ester (5), dihydroaspyrone (6), aspilactonol E (7) and aspilactonol F (8). The structures were determined on the basis of NMR and MS analysis. The isolated compounds were tested for their antiviral activity against H3N2 and EV71 viruses, cytotoxic, and antituberculosis effects. Among them, compounds 2 and 5 showed significant cytotoxicity against ten human cancer cell lines. None of the compounds displayed a significant antiviral activity against H3N2 and EV71 viruses nor antimycobacterial activities.

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Evidence for Agrobacterium-Induced Apoptosis in Maize Cells

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.2000.13.6.649 ◽

2000 ◽

Vol 13 (6) ◽

pp. 649-657 ◽

Cited By ~ 99

Author(s):

Geneviève Hansen

Keyword(s):

Cell Death ◽

Dna Cleavage ◽

Morphological Changes ◽

Plant Cells ◽

Plant Tissues ◽

Apoptotic Pathway ◽

Dicotyledonous Plant ◽

Apoptotic Genes ◽

Baculovirus P35 ◽

Induced Apoptosis

Agrobacterium spp. can genetically transform most dicotyledonous plant cells whereas many monocot species are recalcitrant to Agrobacterium-mediated transformation. One major obstacle is that co-cultivation of Agrobacterium spp. with plant tissues often results in cell death. Report here is that, in maize tissues, this process resembles apoptosis, with characteristic DNA cleavage into oligonucleosomal fragments and morphological changes. Two anti-apoptotic genes from baculovirus, p35 and iap, had the ability to prevent the onset of apoptosis triggered by Agrobacterium spp. in maize tissues. p35 is reported to act as a direct inhibitor of a certain class of proteases (caspase) whereas iap may act upstream to prevent their activation. This evidence raises the possibility that caspase-like proteases may also be involved in the apoptotic pathway in plant cells.

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