Triterpenes from Momordica balsamina (African pumpkin): ABCB1 inhibition and synergistic interaction with doxorubicin in resistant cancer cells.

Aiming at overcoming multidrug resistance (MDR) in cancer, we have been studying Momordica balsamina, a vegetable known as African pumpkin. Five undescribed cucurbitane-type triterpenoids (balsaminaepoxide, balsaminatriol, balsaminoic acid, balsaminal, and balsaminol G) along with five known cucurbitacins were isolated from the methanol extract of Momordica balsamina aerial parts, whose structures were elucidated by spectroscopic data, mainly 1D and 2D NMR experiments. Compounds were evaluated for their ability as P-glycoprotein (P-gp/ABCB1) inhibitors in multidrug resistant human ABCB1-transfected mouse lymphoma cells (L5178Y, MDR) and resistant human colon adenocarcinoma cells (COLO 320), using the rhodamine-123 exclusion test, by flow cytometry. Several compounds, which were found to be non-cytotoxic, strongly inhibited P-gp efflux activity in a dose-dependent manner in both cell models. In MRD mouse lymphoma cells, balsaminol G and karavilagenin B were the most active, while in resistant colon adenocarcinoma cells, the strongest inhibitory activity was found for balsaminaepoxide, balsaminatriol and karavilagenin C, being several-fold more active than the positive control verapamil. In chemosensitivity assays, in a model of combination chemotherapy, selected compounds showed to interact synergistically with doxorubicin, thus substantiating their potential as MDR reversers. The strongest synergistic interaction was found for balsaminal and balsaminol G.

Vitamin A and Wound Healing.

Vitamin A is a general term for retinoids. Vitamin A deficiency leads to a variety of cutaneous manifestations. It also functions as a hormone through retinoic acid receptors altering the activity of multiple cell lines. Pancreatic vitamin A levels are critical for retinoid signaling and normal pancreatic control of glucose. Vitamin A deficiency is more common during infection, and supplementation reduces severe morbidity and mortality from infectious diseases. Vitamin A modulates activities at the cellular level and, via its interrelationship with hormones such as thyroid, insulin, and corticosteroids, has diffuse metabolic effects on the body. It plays an important role in all stages of wound healing. Vitamin A is known for its ability to stimulate epithelial growth, fibroblasts, granulation tissue, angiogenesis, collagen synthesis, epithelialization, and fibroplasia. Local (topical) and systemic supplementation with vitamin A has been proven to increase dermal collagen deposition. There are numerous animal studies and limited human studies regarding physiologic effect of vitamin A on acute or chronic wounds via systemic or topical administration. The most common use of vitamin A supplementation is to offset steroids' effect. When considering supplementation, the potential benefits must be weighed against the risk of harm. Vitamin A toxicity can be critical and even result in death. The evidence for supplementation with vitamin A is currently limited to expert opinion and is not backed up by rigorous trials. There is an acute need for therapeutic trials with vitamin A supplementations.

Effective MDR reversers through phytochemical study of Euphorbia boetica.

INTRODUCTION: Macrocyclic diterpenes from Euphorbia species were found to be promising modulators of multidrug resistance (MDR), a complex phenomenon that hampers the effectiveness of cancer therapy. OBJECTIVE: To find new effective MDR reversers through the phytochemical study of E. boetica, including isolation and molecular derivatisation. MATERIAL AND METHODS: The phytochemical study of E. boetica was performed through chromatographic techniques. Preliminary analysis of crude chromatographic fractions from the methanol extract was carried out by 1 H-NMR in order to prioritise the study of those having macrocyclic diterpenes. Polyamide resin was used to remove chlorophylls. Molecular derivatisation of isolated compounds comprised hydrolysis, reduction and acylation reactions. The structural identification of compounds was performed through analysis of spectroscopic data, mainly one-dimensional- and two-dimensional-NMR. The MDR reversing activity was assessed using a combination of transport and chemosensitivity assays, in mouse lymphoma (L5178Y-MDR) and Colo320 cell models. RESULTS: The 1 H-NMR study of crude fractions and application of a straightforward method to remove chlorophylls, allowed the effortless isolation of two lathyrane-type diterpenes in large amounts, including the new polyester, euphoboetirane B (1). Taking advantage of the chemical functions of 1, 13 new derivatives were prepared. Several compounds showed to be promising modulators of P-glycoprotein (P-gp), in resistant cancer cells. Most of the compounds tested revealed to interact synergistically with doxorubicin. CONCLUSION: These results corroborate the importance of macrocyclic lathyrane diterpenes as effective lead compounds for the reversal of MDR.

Common hydrotherapy practices and the prevalence of burn wound bacterial colonisation at the University Teaching Hospital in Lusaka, Zambia.

BACKGROUND: In many parts of the world, hydrotherapy plays an important role in the management of patients with wounds including burns. Different centers practice hydrotherapy differently. At the University Teaching Hospital in Lusaka, Zambia, burn patients use a common bathtub for cleaning their wounds which theoretically increases the risk of cross-infection, an important source of morbidity and mortality. There is currently no evidence that hydrotherapy as practiced at our institution leads to cross infection among patients with burns. OBJECTIVE: The objective was to determine if our hydrotherapy practice and water plays a role in cross-infection and what organisms cause this infection. METHODS: This was a prospective analytical study. Patients meeting the selection criteria were recruited. Swabs from the burn wounds were collected on admission (day 0), day 4 and day 7. Weekly swabs of the bathtub were also collected, after the tub had been cleaned and declared ready for the next patient. Weekly water samples were also collected. Selected results, for Staphylococcus aureus and Klebsiella pneumoniae, were subjected to further analysis and PCR. Results were analyzed using statistics software, SPSS version 23. RESULTS: In this study, there were 96 participants of which 51 (53.1%) were males and 45 (46.9%) were females. Age distribution ranged from 5months to 91 years. The modal age range was 1 to 2 years. The modal burn percentage was 6%-10%, followed by 11%-15%. Hot water was the cause of burns in 65.6%. S. aureus and K. pneumoniae were the most common organisms isolated. Others were enteric organisms. In terms of readily available antibiotics, there was more sensitivity to Amikacin and Chloramphenicol than Ciprofloxacin (our commonly used antibiotic). The bathtub also had S. aureus and K. pneumoniae, besides enteric organisms. Sixty five point four percent (65.4%) of the Klebsiella were ESBL (Extended Spectrum Beta Lactamase) producers. The tub had samples that were both ESBL producers as well as widely resistant Klebsiella by other means. No growth was obtained from the water samples. Seventy-two point nine percent (72.9%) of the patients were discharged, 19.8% died, while 7.3% left against medical advice. CONCLUSION: Hydrotherapy as currently practiced at the University Teaching Hospital does contribute significantly to cross-infection among burn patients with widely resistant organisms. The main ones are S. aureus and K. pneumoniae. Switching care to a shower mechanism might help eliminate this problem as the study demonstrates that no bacteria were found in the water samples.

Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus.

A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks.

Dregamine and tabernaemontanine derivatives as ABCB1 modulators on resistant cancer cells.

Dregamine (1) and tabernaemontanine (2), two epimeric monoterpene indole alkaloids isolated in large amount from the roots of the African plant Tabernaemontana elegans, were derivatized, yielding ten imine derivatives, as previously described (3-12). In the present study, aiming at increasing the pool of analogues for establishing structure-activity relationships (SAR), compounds 1 and 2 were further submitted to several chemical transformations, yielding thirteen new derivatives (13-25). Their structures were assigned by spectroscopic methods, including 1D and 2D NMR experiments. Compounds 1-25 were evaluated for their effects on the reversion of multidrug resistance (MDR) in cancer cells mediated by P-glycoprotein (P-gp/ABCB1), through combination of functional and chemosensitivity assays, using a human ABCB1-transfected mouse T-lymphoma cell model. SAR analysis showed that different substituents at C-3 and at the indole nitrogen led to different ABCB1 modulatory effects. When compared to the parent compounds, a remarkable enhancement in MDR reversal activity was found for derivatives sharing a new aromatic moiety. Thus, the strongest ability as MDR reversers, and a manifold activity when compared to verapamil, was found for compound 8, the epimeric compounds 9 and 10, and compound 15, bearing pyrazine, bromo-pyridine, and methoxybenzyloxycarbonyl moieties, respectively. In drug combination assays, all compounds tested were revealed to interact synergistically with doxorubicin. Collectively, the results indicate that some of these derivatives may be promising leads for overcoming MDR in cancer.

Triterpenoids from Momordica balsamina: Reversal of ABCB1-mediated multidrug resistance.

The ability as P-glycoprotein (P-gp, ABCB1) modulators of thirty (1-30) triterpenoids of the cucurbitane-type was evaluated on human L5178 mouse T-lymphoma cell line transfected with the human MDR1 gene, through the rhodamine-123 exclusion assay. Compounds (1-26, and 29, 30) were previously obtained from the African medicinal plant Momordica balsamina, through both isolation (1-15) and molecular derivatization (16-26 and 29, 30). Compounds 27-28 are two new karavilagenin C (34) derivatives having succinic acid moieties. Apart from 4, 6, 8, 10 and 11, most of the isolated compounds (1-15) displayed strong MDR reversing activity in a dose-dependent mode, exhibiting a many-fold activity when compared with verapamil, used as positive control. At the lowest concentration tested, compounds 2 and 7 were the most active. However, a decrease of activity was found for the acyl derivatives (16-30). In a chemosensitivity assay, the MDR reversing activity of some of the most active compounds (1-3, 5, 7, 12-15) was further assessed on the same cell model. All the tested compounds, excepting 15, corroborated the results of the transport assay, revealing to synergistically interact with doxorubicin. Structure-activity relationship studies, taking into account previous results, showed that different substitution patterns, at both the tetracyclic nucleus and the side chain, play important role in ABCB1 reversal activity. An optimal lipophilicity was also recognized.

Jatrophane diterpenes and cancer multidrug resistance - ABCB1 efflux modulation and selective cell death induction.

BACKGROUND: Modulation of P-glycoprotein (ABCB1) and evaluation of the collateral sensitivity effect are among the most promising approaches to overcome multidrug resistance (MDR) in cancer. In a previous study, two rare 12,17-cyclojatrophanes (1-2) and other novel jatrophanes (3-4), isolated from Euphorbia welwitschii, were screened for collateral sensitivity effect. Herein, the isolation of another jatrophane (5) is presented, being the broader goal of this work to investigate the role of euphowelwitschines A (1) and B (2), welwitschene (3), epoxywelwitschene (4) and esulatin M (5) as ABCB1 modulators and/or collateral sensitivity agents. METHODS: Compounds 1-5 were evaluated for ABCB1 modulation ability through combination of transport and chemosensitivity assays, using a mouse T-lymphoma MDR1-transfected cell model. Moreover, the nature of interaction of compound 4 with ABCB1 was studied, using an ATPase assay. The MDR-selective antiproliferative activity of compound 5 was evaluated against gastric (EPG85-257) and pancreatic (EPP85-181) human cancer cells and their drug-selected counterparts (EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, EPP85-181RNOV). The drug induced cell death was investigated for compounds 4 and 5, using the annexin V/PI staining and the active caspase-3 assay. RESULTS: The jatrophanes 1-5 were able to modulate the efflux activity of ABCB1, and at 2µM, 3-5 maintained the strong modulator profile. Structure activity results indicated that high conformational flexibility of the twelve-membered ring of compounds 3-5 favored ABCB1 modulation, in contrast to the tetracyclic scaffold of compounds 1 and 2. The effects of epoxywelwitschene (4) on the ATPase activity of ABCB1 showed it to interact with the transporter and to be able to reduce the transport of a second subtrate. Drug combination experiments also corroborated the anti-MDR potential of these diterpenes due to their synergistic interaction with doxorubicin (combination index <0.7). Esulatin M (5) showed a strong MDR-selective antiproliferative activity against EPG85-257RDB and EPP85-181RDB cells, with IC50 of 1.8 and 4.8 µM, respectively. Compounds 4 and 5 induced apoptosis via caspase-3 activation. A significant discrimination was observed between the resistant cell lines and parental cells. CONCLUSIONS: This study strengthens the role of jatrophane diterpenes as lead candidates for the development of MDR reversal agents, higlighting the action of compounds 4 and 5.

Isolation and Structure Elucidation, Molecular Docking Studies of Screlotiumol from Soil Borne Fungi Screlotium rolfsii and their Reversal of Multidrug Resistance in Mouse Lymphoma Cells.

A new compound namely (13-(3,3-dihydroxypropyl)-1,6-dihydroxy-3,4-dihydro-1H-isochromen-8(5H)-one (1) was isolated from an ethyl acetate extract of the borne fungi Screlotium rolfsii. Its chemical structure was elucidated by spectroscopic analysis. Screlotiumol 1 were evaluated for their effects on the reversion of multidrug resistant (MDR) mediated by P-glycoprotein (P-gp) of the soil borne fungi. The multidrug resistant P-glycoprotein is a target for chemotherapeutic drugs in cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma which showed excellent MDR reversing effect in a dose dependent manner against mouse T-lymphoma cell line. Moreover, molecular docking studies of compound-1 also showed better results as compared with the standard. Therefore the preliminary results obtained from this study suggest that screlotiumol 1 could be used as a potential agent for the treatment of cancer.

Reversal of Multidrug Resistance and Computational Studies of Pistagremic Acid Isolated from Pistacia integerrima.

Pistagremic acid (PA) is a bioactive triterpenoid isolated from various parts of Pistacia integerrima plants. The aim of this research was to investigate PA for reversion of multidrug resistant (MDR) mediated by P-glycoprotein using rhodamine-123 exclusion study on a multidrug resistant human ABCB1 (ATP-binding cassette, sub-family B, member 1) gene-transfected mouse T-lymphoma cell line in vitro. Results were similar to those with verapamil as a positive control. Docking studies of PA and standard Rhodamine123 were carried out against a P-gp crystal structure which showed satisfactory results. Actually, PA cannot bind exactly where co-crystallized ligand of P-gp is already present. However, the docking study predicted that if a compound gives a lesser score then it may have some potency. The docking scores of PA and Rhodamine were similar. Therefore, we can conclude that there are certain important chemical features of PA which are responsible for the inhibiting potency of P-gp.

Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia integerrima.

Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine- 123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.

Fluorinated ß-Diketo Phosphorus Ylides Are Novel Inhibitors of the ABCB1 Efflux Pump of Cancer Cells.

Efflux pump inhibitors are attractive compounds that reverse multidrug resistance (MDR) in cancer cells. In the present study, 10 phosphorus ylides (P-ylides) were compared based on their MDR-reverting activity in human ATP-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) gene-transfected L5178Y mouse T-lymphoma cells. Among them, three P-ylides, Ph3P=C(COCF3)COPh, Ph3P=C(COC2F5)COPh and Ph3P=C(COC3F7)COPh were identified as selectively modulating the ABCB1 pump. These compounds, with low cytotoxicity against mouse T-lymphoma cells, exhibited more potency than the positive control ABCB1 inhibitor verapamil.

Nutrition and Chronic Wounds.

Significance: Nutrition is one of the most basic of medical issues and is often ignored as a problem in the management of our chronic wound patients. Unfortunately, malnutrition is widespread in our geriatric patients even in nursing homes in developed countries. Attention to basic nutrition and providing appropriate supplements may assist in the healing of our chronic wounds. Recent Advances: Recent research has revealed the epidemiology of malnutrition in developed countries, the similarities to malnutrition in developing countries, and some of the physiologic and sociologic causes for this problem. More information is now available on the biochemical effects of nutrient deficiency and supplementation with macronutrients and micronutrients. In some cases, administration of isolated nutrients beyond recommended amounts for healthy individuals may have a pharmacologic effect to help wounds heal. Critical Issues: Much of the knowledge of the nutritional support of chronic wounds is based on information that has been obtained from trauma management. Due to the demographic differences of the patients and differences in the physiology of acute and chronic wounds, it is not logical to assume that all aspects of nutritional support are identical in these patient groups. Before providing specific nutritional supplements, appropriate assessments of patient general nutritional status and the reasons for malnutrition must be obtained or specific nutrient supplementation will not be utilized. Future Directions: Future research must concentrate on the biochemical and physiologic differences of the acute and chronic wounds and the interaction with specific supplements, such as antioxidants, vitamin A, and vitamin D.

Diterpenes from Euphorbia piscatoria: synergistic interaction of Lathyranes with doxorubicin on resistant cancer cells.

Four new diterpenes were isolated from the methanolic extract of Euphorbia piscatoria, two ent-abietanes (1, 2) and two lathyrane-type macrocyclic diterpenes (3, 4), along with three known diterpenes (5-7). Their structures were characterized by spectroscopic methods, mainly 1D and 2D NMR ((1)H, (13)C, DEPT, COSY, HMBC, HMQC, and NOESY) experiments. Compound 2, with an unusual structure, might be considered intermediate in the biosynthesis of ent-abietane α,ß-unsaturated lactones, commonly found in Euphorbia species. Therefore, a possible biogenetic pathway is proposed. The MDR reversal potential of macrocyclic diterpenes 3-5 was evaluated through a drug combination assay, using the L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. Compounds 3-5 were able to enhance, synergistically, the antiproliferative activity of doxorubicin (combination indexes < 0.5). Moreover, compounds 1-6 were also assessed for their antiproliferative activity on human MDR cancer cell models, namely gastric, pancreatic, and colon. Weak antiproliferative activity was observed for compounds 1 (IC50 = 66.02 ± 7.10 µM) and 4 (IC50 = 39.51 ± 3.82 µM) on the MDR gastric cell line.

Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis.

Over a period of 14 years, the authors have studied thioridazine, an old neuroleptic, that has been shown to have in vitro activity against intracellular Mycobacterium tuberculosis, regardless of its antibiotic resistance status, thioridazine cures infected mice of antibiotic-susceptible and multidrug-resistant tuberculosis (TB) infections and, when used in combination with antibiotics used for therapy of TB, renders the organism significantly more susceptible. This article will describe the authors' further work and the mechanisms by which thioridazine alone and in combination with antibiotics cures an extensively drug-resistant infection and why it is expected to cure totally drug-resistant TB infections as well. The concepts presented are entirely new and because they focus on the activation of killing by nonkilling macrophages where M. tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic-resistant status, effective therapy of any antibiotic-resistant TB infection is possible.

The activity of 16 new hydantoin compounds on the intrinsic and overexpressed efflux pump system of Staphylococcus aureus.

AIM: To evaluate a new series of 16 hydantoin derivatives for activity against the intrinsic and overexpressed efflux pumps of the ATTC 25923 Staphylococcus aureus and the clinical Staphylococcus aureus HPV-107 strain, respectively. MATERIALS AND METHODS: The hydantoin compounds were evaluated for activity against the efflux pumps of the ATTC 25923 S. aureus and the clinical S. aureus HPV-107 strains by the aid of the automated ethidium bromide method. Compounds that inhibited the efflux pumps of either strain were evaluated for ability to reduce or reverse resistance of these strains to oxacillin. RESULTS: Although most of the hydantoins inhibited the efflux pumps of the ATTC strain, none reduced the resistance of this strain to oxacillin. In contrast, the inhibition of the Qac efflux pump present in HPV-107 was inhibited to some degree, by much higher concentrations of the hydantoin compounds than that needed for similar activity against the ATTC strain; only hydantoin PI8a significantly reduced the minimum inhibitory concentration of oxacillin against the HPV-107 strain. CONCLUSION: Hydantoin compound PI8a may have potential for therapy of a methicillin-resistant S. aureus infection whose multidrug-resistant phenotype is due to overexpression of an efflux pump.

Activity of fourteen new hydantoin compounds on the human ABCB1 efflux pump.

BACKGROUND: Multidrug resistance (MDR) is one of the major concerns in the treatment of cancer and one of the major causes of therapy failure. The overexpression of an ABC transporter, the ABCB1, is often associated with MDR in cancer. Previously it was observed that hydantoin compounds can modulate the activity of the ABCB1 pump. MATERIALS AND METHODS: Fourteen hydantoin derivatives were synthesized and studied for their capacity to increase accumulation of ethidium bromide (EB) by mouse lymphoma cancer cells that were transfected with the human ABCB1 gene and overexpress the human ABCB1 pump. RESULTS: It was observed that the accumulation of EB by the cells in the presence of four of the newly synthesized hydantoins was strongly increased. Similar but milder effects were also observed for the other seven hydantoins; the remaining three had no activity. CONCLUSION: The 14 hydantoin compounds studied belong to three different structural groups. Structure-activity relationships were studied and important molecular substituents that were possibly responsible for increased the activity of the molecules were identified. This important information may lead to the continuation of our work and to the future synthesis of more active compounds.

Alkaloids derived from genus Veratrum and Peganum of Mongolian origin as multidrug resistance inhibitors of cancer cells.

Alkaloids comprise one of the largest groups of plant secondary metabolites including vinca alkaloids. The ability of six alkaloids from Veratrum lobelianum, one from Veratrum nigrum and three from Peganum nigellastrum to modify transport activity of MDR1 was studied. Flow-cytometry in a multidrug-resistant human MDR1-gene-transfected mouse lymphoma cells (L5178Y) was applied. The inhibition of multidrug resistance was investigated by measuring the accumulation of rhodamine-123 in cancer cells. Veralosinine and veranigrine were the most effective resistance modifiers. In a checkerboard method veralosinine and veranigrine enhanced the antiproliferative effects of doxorubicin on MDR cells in combination. The structure-activity relationships were discussed.

Steroidal alkaloids of Veratrum lobelianum Bernh. and Veratrum nigrum L.

Twelve steroidal alkaloids were isolated from four populations of Veratrum lobelianum Bernh. and Veratrum nigrum L. Full NMR data for veralosinine (1), and extensive 1H NMR data for veralosine (3) and teinemine (5) are presented here for the first time. (+/-)-15-O-(2-Methylbutyroyl)germine (10) is undescribed up to now. The antiproliferative activities of veranigrine, veralosinine, and neogermitrine have shown that they are a perspective for further studies.

Antitumor-promoting activity of lignans: inhibition of human cytomegalovirus IE gene expression.

BACKGROUND: Chemoprevention is a promising new approach to cancer prevention. Since the beginning of chemoprevention studies, short-term in vitro models used in the study of carcinogenesis have been applied in the identification of antitumor-promoting agents. MATERIALS AND METHODS: The lignans threo-4,4'-dihydroxy-3-methoxylignan, (-)-dihydroguaiaretic acid, 4'-hydroxy-3,3',4-trimethoxylignan, 3,3',4,4'-tetramethoxylignan, 4,4'-diacetyl-3,3'-dimethoxylignan, talaumidin, heliobuphthalmin, (-)-dihydro-cubebin, and hinokinin were evaluated for their ability to inhibit human cytomegalovirus (HCMV) IE-antigen expression in lung cancer cells (A549). RESULTS: Most of the evaluated compounds reduced IE-antigen expression of HCMV, the best result being obtained with 4,4'-dihydroxy-3-methoxylignan. However, a dose-dependent significant increase of IE-antigen expression was found for the derivative (-)-dihydrocubebin. CONCLUSION: The results of this study suggest that some of these lignans might be valuable as potential cancer chemopreventive agents.