• Corydalis heterocarpa
• Human dermal fibroblast
• Isopimpinellin
• MMP
• Photoaging

• ASE extraction
• Ammi majus fruits
• HPLC/DAD quantitative analysis
• LC/CPC isolation
• antiproliferative activity
• apoptosis
• colorectal adenocarcinoma (HT29 and SW620)
• isopimpinellin
• multiple myeloma (RPMI8226 and U266)
• osteosarcoma (Saos-2 and HOS)

• Humans
• Fruit/chemistry
• Cell Line, Tumor
• Furocoumarins/pharmacology
• Furocoumarins/chemistry
• Plant Extracts/pharmacology
• Plant Extracts/chemistry
• Ammi/chemistry
• Cell Proliferation/drug effects
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/chemistry
• Apoptosis/drug effects
• Chromatography, High Pressure Liquid
• Cell Survival/drug effects

• anticancer
• breast cancer
• coumarin
• drug development
• structure–activity relationship

• NFO-2018-19-OBCPUN-74306 University Grants Commission, India

• CYP1A1
• CYP1A2
• cytochrome P450
• inhibitors
• structure-activity relationships (SARs)

• Animals
• Humans
• Cytochrome P-450 CYP1A1/metabolism
• Cytochrome P-450 CYP1A2/metabolism
• Cytochrome P-450 Enzyme System/metabolism
• Mammals/metabolism

• 81891012 National Natural Science Foundation of China
• 81803627 National Natural Science Foundation of China
• 82273897 National Natural Science Foundation of China
• U20A20405 National Natural Science Foundation of China
• 81922070 National Natural Science Foundation of China
• 81973286 National Natural Science Foundation of China
• 2021-I2M-1-071,2022-I2M-2-001 CAMS Innovation Fund for Medical Sciences
• 21S21900600 Shanghai Science and Technology Innovation Action Plans
• 2022CX005 Shanghai Municipal Health Commission's TCM research project
• ZYYCXTD-D-202004 Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine

• CYP1 enzymes
• Estradiol
• bioactivation
• biotransformation
• enzymatic induction
• enzymatic inhibition
• structure–activity relationships

• FAK/Src/Rac1 pathway
• ITGα3
• ITGβ5
• Wenshen Zhuanggu Formula
• breast cancer
• metastasis
• osthole

Cancers of the gastrointestinal (GI) tract are often life-threatening malignancies, which can be a severe burden to the health care system. Globally, the mortality rate from gastrointestinal tumors has been increasing due to the lack of adequate diagnostic, prognostic, and therapeutic measures to combat these tumors. Coumarin is a natural product with remarkable antitumor activity, and it is widely found in various natural plant sources. Researchers have explored coumarin and its related derivatives to investigate their antitumor activity, and the potential molecular mechanisms involved. These mechanisms include hormone antagonists, alkylating agents, inhibitors of angiogenesis, inhibitors of topoisomerase, inducers of apoptosis, agents with antimitotic activity, telomerase inhibitors, inhibitors of human carbonic anhydrase, as well as other potential mechanisms. Consequently, drug design and discovery scientists and medicinal chemists have collaborated to identify new coumarin-related agents in order to produce more effective antitumor drugs against GI cancers. Herein, we summarize the therapeutic effects of coumarin and its derivatives against GI cancer.

• Coumarin – Benzimidazole
• gastric cancer
• gastrointestinal cancer
• natural compound
• therapy

• Angiogenesis
• HUVEC
• Isopimpinellin
• Zebrafish
• miRNA

Prostate cancer is the second leading cause of cancer related death in American men. Several therapies have been developed to treat advanced prostate cancer, but these therapies often have severe side effects. To improve the outcome with fewer side effects we focused on the furanocoumarin bergamottin, a natural product found in grapefruit juice and a potent CYP3A inhibitor. Our recent studies have shown that CYP3A5 inhibition can block androgen receptor (AR) signaling, critical for prostate cancer growth. We observed that bergamottin reduces prostate cancer (PC) cell growth by decreasing both total and nuclear AR (AR activation) reducing downstream AR signaling. Bergamottin’s role in reducing AR activation was confirmed by confocal microscopy studies and reduction in prostate specific antigen (PSA) levels, which is a marker for prostate cancer. Further studies revealed that bergamottin promotes cell cycle block and accumulates G0/G1 cells. The cell cycle block was accompanied with reduction in cyclin D, cyclin B, CDK4, P-cdc2 (Y15) and P-wee1 (S642). We also observed that bergamottin triggers apoptosis in prostate cancer cell lines as evident by TUNEL staining and PARP cleavage. Our data suggests that bergamottin may suppress prostate cancer growth, especially in African American (AA) patients carrying wild type CYP3A5 often presenting aggressive disease.

• apoptosis
• autophagy
• cell cycle arrest
• furanocoumarin
• metastasis

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Autophagy/drug effects
• Biological Availability
• Cell Cycle Checkpoints/drug effects
• Furocoumarins/chemistry
• Furocoumarins/pharmacology
• Furocoumarins/therapeutic use
• Humans
• Neoplasms/drug therapy
• Neoplasms/pathology

• Hibiscus sabdariffa
• bioequivalence
• caffeine
• herb-drug interaction
• human
• pharmacokinetics

• Angelica archangelica
• Angelicin
• Apoptosis
• Breast cancer
• Cell death
• Umbelliferae

• Angelica archangelica/chemistry
• Animals
• Antineoplastic Agents, Phytogenic/administration & dosage
• Antineoplastic Agents, Phytogenic/chemistry
• Apoptosis/drug effects
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/physiopathology
• Caspase 3/genetics
• Caspase 3/metabolism
• Cell Proliferation/drug effects
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Plant Extracts/administration & dosage
• Plant Extracts/chemistry
• Rhizome/chemistry
• bcl-2-Associated X Protein/genetics
• bcl-2-Associated X Protein/metabolism

• Apiaceae
• Biological targets
• Cancer
• Coumarins
• Inflammation
• Neuroprotection
• Oxyprenylated secondary metabolites
• Rutaceae

• bergamottin
• cancer
• chemoprevention
• phytochemicals

• Anti-Inflammatory Agents/chemistry
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Citrus paradisi/chemistry
• Cytochrome P-450 Enzyme Inhibitors/chemistry
• Cytochrome P-450 Enzyme Inhibitors/pharmacology
• Cytochrome P-450 Enzyme Inhibitors/therapeutic use
• Furocoumarins/chemistry
• Furocoumarins/pharmacology
• Furocoumarins/therapeutic use
• Humans
• Molecular Structure
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/prevention & control
• Neoplasms/therapy
• Oxidative Stress/drug effects

• apoptosis
• cell cycle
• flow cytometry
• hesperidin
• osteosarcoma

• apoptosis
• isoimperatorin
• mitochondrial pathway

• Rac1 signaling
• glioma
• invasiveness
• phytochemical

The aim of the present study was to evaluate in vitro effects of dietary phytochemicals naringenin, quercetin, and sesamin on the activities of ethoxy- (EROD; CYP1A) and benzyloxy- (BROD; CYP3A) resorufin O-dealkylases after the exposure to the cocktail of persistent organic pollutants (POPs). CD-1 mice were exposed from weaning, through gestation and lactation to a defined mixture of POPs. Hepatic microsomes were prepared from their female offspring at postnatal day 42. Hepatic EROD and BROD activity were evaluated in the presence of quercetin, naringenin, and sesamin at nine concentrations from 5 to 100000 nM. EROD activity was strongly inhibited by quercetin with Ki values from 1.7 to 2.6 μM. BROD activity was inhibited by quercetin with Ki values from 64.9 to 75.3 μM and naringenin with Ki values from 39.3 to 45.8 μM. The IC₅₀ and Ki values did not differ between the groups of mice with different levels of POPs exposure in any of the experimental sets. Sesamin did not inhibit either EROD or BROD. We concluded that the interactions of quercetin and naringenin with CYP1A and CYP3A in mice liver were not affected by the levels of POPs exposure.

• Cattle
• Cooperia punctata
• Coumarin
• Phytochemicals
• SEM
• TEM

A variety of xenobiotic chemicals, such as polycyclic aromatic hydrocarbons (PAHs), aryl- and heterocyclic amines and tobacco related nitrosamines, are ubiquitous environmental carcinogens and are required to be activated to chemically reactive metabolites by xenobiotic-metabolizing enzymes, including cytochrome P450 (P450 or CYP), in order to initiate cell transformation. Of various human P450 enzymes determined to date, CYP1A1, 1A2, 1B1, 2A13, 2A6, 2E1, and 3A4 are reported to play critical roles in the bioactivation of these carcinogenic chemicals. In vivo studies have shown that disruption of Cyp1b1 and Cyp2a5 genes in mice resulted in suppression of tumor formation caused by 7,12-dimethylbenz[a]anthracene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, respectively. In addition, specific inhibitors for CYP1 and 2A enzymes are able to suppress tumor formation caused by several carcinogens in experimental animals in vivo, when these inhibitors are applied before or just after the administration of carcinogens. In this review, we describe recent progress, including our own studies done during past decade, on the nature of inhibitors of human CYP1 and CYP2A enzymes that have been shown to activate carcinogenic PAHs and tobacco-related nitrosamines, respectively, in humans. The inhibitors considered here include a variety of carcinogenic and/or non-carcinogenic PAHs and acethylenic PAHs, many flavonoid derivatives, derivatives of naphthalene, phenanthrene, biphenyl, and pyrene and chemopreventive organoselenium compounds, such as benzyl selenocyanate and benzyl selenocyanate; o-XSC, 1,2-, 1,3-, and 1,4-phenylenebis( methylene)selenocyanate.

• Chemical carcinogenesis
• Cytochrome P450
• Enzyme inhibition
• Metabolic activation
• Polycyclic aromatic hydrocarbons
• Tobacco-related nitrosamines

Benzo[a]pyrene (BaP) is a well-studied pro-carcinogen that is metabolically activated by cytochrome P450 enzymes. Cytochrome P4501A1 (CYP1A1) has been considered to play a central role in the activation step, which is essential for the formation of DNA adducts. This enzyme is strongly induced by many different chemical agents, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which binds to the aryl hydrocarbon receptor (AhR). Therefore, AhR activators are suspected to have the potential to aggravate the toxicity of BaP through the induction of CYP1A1. Besides, CYP1A1 inhibitors, including its substrates, are estimated to have preventive effects against BaP toxicity. However, strangely, increased hepatic BaP–DNA adduct levels have been reported in Cyp1a1 knockout mice. Moreover, numerous reports describe that concomitant treatment of AhR activators reduced BaP–DNA adduct formation. In an experiment using several human cell lines, TCDD had diverse modulatory effects on BaP–DNA adducts, both enhancing and inhibiting their formation. In this review, we focus on the factors that could influence the BaP–DNA adduct formation. To interpret these complicated outcomes, we propose a hypothesis that CYP1A1 is a key enzyme for both generation and reduction of (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), the major carcinogenic intermediate of BaP. Conversely, CYP1B1 is thought to contribute only to the metabolic activation of BaP related to carcinogenesis.

• Aryl hydrocarbon receptor
• Benzo[a]pyrene
• Cytochrome P450
• DNA adduct

Five polysaccharides, namely ADPs-1a, ADPs-1b, ADPs-2, ADPs-3a and ADPs-3b, were extracted from Angelicae dahuricae Radix, purified, and identified by high performance gel permeation chromatography (HPSEC), gas chromatography (GC), Fourier transform infrared (FT-IR) spectrometer and nuclear magnetic resonance spectra (NMR), including the determination of procoagulant activity in vitro. The average molecular weight (Mw) of the polysaccharides was 153,800, 8312, 111,700, 3766 and 96,680 g/mol, respectively. Coagulation assays indicated that ADPs-1b, ADPs-2, ADPs-3a and ADPs-3b had procoagulant activities. ADPs-1b exerted the procoagulant activities through intrinsic pathway, extrinsic pathway and increased the content of FIB in vitro. ADPs-2 exerted the procoagulant activities through intrinsic pathway and extrinsic pathway. ADPs-3a had procoagulant activities and the activity was associated with the intrinsic pathway and increased the content of FIB. ADPs-3b exerted the activities through extrinsic pathway and increased the content of FIB.

• Angelicae dahuricae Radix
• Polysaccharides
• Procoagulant

• Furanocoumarin
• Imperatorin
• Psoralen derivatives

• magydaris tomentosa
• coumarins
• furanocoumarins
• xanthotoxin
• xanthotoxol
• isopimpinellin
• osthole
• bergaptene
• mcf-7

• Alkanes/chemistry
• Animals
• Apiaceae/chemistry
• Cell Death/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Coumarins/chemistry
• Flowers/chemistry
• Gas Chromatography-Mass Spectrometry
• Humans
• Mice
• Plant Extracts/pharmacology

This review examines the biological properties of coumarins, widely distributed at the highest levels in the fruit, followed by the roots, stems and leaves, by considering their beneficial effects in the prevention of some diseases and as anti-cancer agents. These compounds are well known photosensitizing drugs which have been used as pharmaceuticals for a broad number of therapeutic applications requiring cell division inhibitors. Despite this, even in the absence of ultraviolet rays they are active. The current paper mainly focuses on the effects of psoralens on human breast cancer as they are able to influence many aspects of cell behavior, such as cell growth, survival and apoptosis. In addition, analytical and pharmacological data have demonstrated that psoralens antagonize some metabolizing enzymes, affect estrogen receptor stability and counteract cell invasiveness as well as cancer drug resistance. The scientific findings summarized highlight the pleiotropic functions of phytochemical drugs, given that recently their target signals and how these are modified in the cells have been identified. The encouraging results in this field suggest that multiple modulating strategies based on coumarin drugs in combination with canonical chemotherapeutic agents or radiotherapy could be a useful approach to address the treatment of many types of cancer.

• Psoralens
• Breast tumor
• Bergapten
• Growth factors
• Estrogens

The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3′-Ethynylflavone, 4′-ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (K_I values of 0.035–0.056 μM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (K_I value of 0.51 μM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4′-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a K_i value of 0.035 μM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.

Helicobacter pylori (H. pylori) is one of the most widespread human pathogens, and plays major roles in chronic gastritis and gastric cancer. CD74 of gastric epithelial cells has recently been identified as an adhesion molecule to urease in H. pylori. In this study, we found that CD74 is highly expressed in a constitutive manner in NCI-N87 human gastric carcinoma cells at both the protein and mRNA levels as compared with Hs738St./Int fetal gastric cells. Subsequently, a novel cell-based ELISA able to rapidly screen the suppressive agents of CD74 expression was established. NCI-N87 cells were treated separately with 25 different food phytochemicals (4–100 µM) for 48 h and subjected to our novel assay. From those results, a citrus coumarin, bergamottin, was indicated to be the most promising compound with an LC₅₀/IC₅₀ value greater than 7.1, followed by luteolin (>5.4), nobiletin (>5.3), and quercetin (>5.1). Our findings suggest that these CD74 suppressants are unique candidates for preventing H. pylori adhesion and subsequent infection with reasonable action mechanisms.

• CD74
• Helicobacter pylori
• adhesion
• bergamottin
• cell-based ELISA

Thymoquinone (TQ) is a compound extracted from Black Caraway seeds of Nigella Sativa and is active against various cancers. Cisplatin (CDDP) is the most active chemotherapeutic agent in Lung Cancer. Here we report activity of TQ against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines alone and in combination with Cisplatin (CDDP).

For proliferation MTT assay, cell viability trypan blue assay and for apoptosis Annexin-V FITC assay were used in NCI-H460 and NCI-H146 cell lines. Inhibition of invasion by TQ was assessed using Matrigel assay and its affect on release of various cytokines was determined using RayBio Human Cytokine detection kit. Mouse xenograft model using NCI-H460 was used to determine in vivo activity of TQ and CDDP. Inhibition of LPS induced NF-κB expression by TQ was determined using transgenic mice expressing a luciferase reporter.

TQ was able to inhibit cell proliferation, reduce cell viability and induce apoptosis. TQ at 100 μM and CDDP at 5 μM inhibited cell proliferation by nearly 90% and the combination showed synergism. TQ was able to induced apoptosis in both NCI-H460 and NCI-H146 cell lines. TQ also appears to affect the extracellular environment inhibiting invasion and reducing the production of two cytokines ENA-78 and Gro-alpha which are involved in neo-angiogenesis. Using a mouse xenograft model we were able to demonstrate that combination of TQ and CDDP was well tolerated and significantly reduced tumor volume and tumor weight without additional toxicity to the mice. In the combination arms (TQ5 mg/kg/Cis 2.5 mg/kg) tumor volume was reduced by 59% and (TQ20 mg/kg/Cis 2.5 mg/kg) by 79% as compared to control which is consistent with in vitro data. TQ down regulated NF-κB expression which may explain its various cellular activities and this activity may prove useful in overcoming CDDP resistance from over expression of NF-κB.

Thus TQ and CDDP appear to be an active therapeutic combination in lung cancer.

• Anthracenes/toxicity
• Anticarcinogenic Agents/chemistry
• Anticarcinogenic Agents/pharmacology
• Benz(a)Anthracenes/toxicity
• Brassica/chemistry
• Breast Neoplasms/metabolism
• Carcinogens/toxicity
• Cell Line, Tumor
• Cytochrome P-450 CYP1A1/drug effects
• Cytochrome P-450 CYP1A1/metabolism
• Cytochrome P-450 CYP1A2/drug effects
• Cytochrome P-450 CYP1A2/metabolism
• Enzyme Induction/drug effects
• Female
• Humans
• Isothiocyanates
• Structure-Activity Relationship
• Sulfoxides
• Thiocyanates/chemistry
• Thiocyanates/pharmacology

• Analysis of Variance
• Animals
• Anticonvulsants/therapeutic use
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Electroshock/adverse effects
• Furocoumarins/therapeutic use
• Male
• Mice
• Seizures/drug therapy
• Seizures/etiology
• Time Factors

• Acetylcysteine/pharmacology
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/therapeutic use
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Ascorbic Acid/pharmacology
• Benzyl Alcohols
• Breast Neoplasms/drug therapy
• Breast Neoplasms/enzymology
• Breast Neoplasms/pathology
• Caspase 3/biosynthesis
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Chromans/pharmacology
• Dose-Response Relationship, Drug
• Enzyme Induction
• Female
• Humans
• Terpenes/pharmacology
• Terpenes/therapeutic use
• Time Factors

• 1K22CA102005-01A2 NCI NIH HHS

• Carcinogens, Environmental/chemistry
• Carcinogens, Environmental/metabolism
• Cytochrome P-450 CYP1A1/antagonists & inhibitors
• Cytochrome P-450 CYP1A1/genetics
• Cytochrome P-450 CYP1A1/metabolism
• Cytochrome P-450 CYP1A2/genetics
• Cytochrome P-450 CYP1A2/metabolism
• Cytochrome P-450 CYP1A2 Inhibitors
• Humans
• Inactivation, Metabolic
• Polycyclic Aromatic Hydrocarbons/chemistry
• Polycyclic Aromatic Hydrocarbons/metabolism
• Xenobiotics/chemistry
• Xenobiotics/metabolism