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1'S-1'-acetoxyeugenol acetate: a new chemotherapeutic natural compound against MCF-7 human breast cancer cells

Hasima N, Aun LI, Azmi MN, Aziz AN, Thirthagiri E, Ibrahim H, et al.

Phytomedicine, 2010 Oct;17(12):935-9.
PMID: 20729047 DOI: 10.1016/j.phymed.2010.03.011

Medicinal plants containing active natural compounds have been used as an alternative treatment for cancer patients in many parts of the world especially in Asia (Itharat et al. 2004). In this report, we describe the cytotoxic and apoptotic properties of 1'S-1'-acetoxyeugenol acetate (AEA), an analogue of 1'S-1'-acetoxychavicol acetate (ACA), isolated from the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) on human breast cancer cells. Data from MTT cell viability assays indicated that AEA induced both time- and dose-dependent cytotoxicity with an IC(50) value of 14.0 μM within 36 h of treatment on MCF-7 cells, but not in HMEC normal control cells. Both annexin V-FITC/PI flow cytometric analysis and DNA fragmentation assays confirmed that AEA induced cell death via apoptosis. AEA was also found to induce cell cycle arrest in MCF-7 cells at the G(0)/G(1) phase with no adverse cell cycle arrest effects on HMEC normal control cells. It was concluded that AEA isolated from the Malaysian tropical ginger represents a potential chemotherapeutic agent against human breast cancer cells with higher cytotoxicity potency than its analogue, ACA.
Acute toxicity of Orthosiphon stamineus Benth standardized extract in Sprague Dawley rats

Abdullah NR, Ismail Z, Ismail Z

Phytomedicine, 2009 Mar;16(2-3):222-6.
PMID: 17498941

The acute toxicity of standardized extract of Orthosiphon stamineus was studied in Sprague Dawley rats. The rats were administered a single dose of 5000 mg/kg body weight (BW) orally on Day 0 and observed for 14 days. There were no deaths recorded and the animals did not show signs of toxicity during the experimental period. The effect of the extract on general behavior, BW, food and water intake, relative organ weight per 100 g BW, hematology and clinical biochemistry were measured. All the parameters measured were unaffected as compared to the control. The acute toxicity LD(50) was estimated to be > 5000 mg/kg BW.
Alpha-tomatine synergises with paclitaxel to enhance apoptosis of androgen-independent human prostate cancer PC-3 cells in vitro and in vivo

Lee ST, Wong PF, Hooper JD, Mustafa MR

Phytomedicine, 2013 Nov 15;20(14):1297-305.
PMID: 23920276 DOI: 10.1016/j.phymed.2013.07.002

Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment.
Anti-inflammatory agents from Sandoricum koetjape Merr

Rasadah MA, Khozirah S, Aznie AA, Nik MM

Phytomedicine, 2004 Feb;11(2-3):261-3.
PMID: 15070182

The anti-inflammatory activity of the stem extracts of Sandoricum koetjape was investigated on topical administration using the TPA (tetradecanoylphorbol acetate)-induced mouse ear inflammation model. Bioassay-guided chromatographic fractionation of active fractions led to the isolation 3-oxo-12-oleanen-29-oic acid and katonic acid as the bioactive principles responsible for the anti-inflammatory acitivity. The percentage of inhibition exhibited by 3-oxo-12-oleanen-29-oic acid was almost equivalent to indomethacin.
Fulltext Anti-ulcerogenic activity of dentatin from clausena excavata Burm.f. against ethanol-induced gastric ulcer in rats: Possible role of mucus and anti-oxidant effect

Sidahmed HMA, Vadivelu J, Loke MF, Arbab IA, Abdul B, Sukari MA, et al.

Phytomedicine, 2019 Mar 01;55:31-39.
PMID: 30668441 DOI: 10.1016/j.phymed.2018.06.036

BACKGROUND: Clausena excavata Burm.f. (Rutaceae) has been used for the treatment of stomach disorders including peptic ulcer.
PURPOSE: In this study, we aimed to investigate dentatin isolated from C. excavata Burm.f., for anti-ulcer activity against ethanol ulcer model in rats.
METHODS: Gastric acid output, ulcer index, serum profile, histological evaluation using Hematoxylin and eosin (HE), periodic acid Schiff base stainings and immunohistochemical localization for heat shock proteins 70 (HSP70) were all investigated. Possible involvement of reduced glutathione (GSH), lipid peroxidation, prostaglandin E2 (PGE2), superoxide dismutase (SOD) enzymes, radical scavenging, and anti-Helicobacter pylori activity were investigated.
RESULTS: Dentatin showed anti-secretory activity against the pylorus ligature model and protected the gastric mucosa from ethanol ulceration, as revealed by the improved macroscopic and histological appearance. Dentatin significantly increased the gastric homogenate content of PGE2 GSH and SOD. Dentatin inhibited the lipid peroxidation as revealed by the reduced gastric content of malondialdehyde (MDA). Moreover, dentatin up-regulated HSP70 expression. However, dentatin showed insignificant anti-H. pylori activity.
CONCLUSION: Dentatin possesses gastro-protective activity, which could be attributed to the anti-secretory, mucus production, anti-oxidant, and HSP70 activities.
Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression

Idayu NF, Hidayat MT, Moklas MA, Sharida F, Raudzah AR, Shamima AR, et al.

Phytomedicine, 2011 Mar 15;18(5):402-7.
PMID: 20869223 DOI: 10.1016/j.phymed.2010.08.011

Mitragyna speciosa Korth. leaves have been used for decades as a traditional medicine to treat diarrhea, diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of Southeast Asia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychological disorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST), two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrine system of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration of mice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility in the FST and TST with changes in motor activity of mice treated with mitragynine. In the present study, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobility time of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover, mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at dose of 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts an antidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to be mediated by an interaction with neuroendocrine HPA axis systems.
Antimicrobial and antiinflammatory activities of extracts and constituents of Oroxylum indicum (L.) Vent

Mat Ali R, Houghton PJ, Raman A, Hoult JR

Phytomedicine, 1998 Oct;5(5):375-81.
PMID: 23195987 DOI: 10.1016/S0944-7113(98)80020-2

Dichloromethane extracts of the stembark and root of Oroxylum indicum were found to have antimicrobial activities against Gram positive bacteria (Bacillus subtilis and Staphylococcus aureus), Gramnegative bacteria (Escherichia coli and Pseudomonas aeruginosa) and a yeast (Candida albicans). Bioassay-guided chromatographic fractionation led to the isolation of flavonoids (bacailein and chrysin) and a naphthoquinone, lapachol. Lapachol was found active against the Gram-positive bacteria, 5 μg giving a zone of inhibition equivalent to that shown by 5 μg streptomycin, whereas 5 μg chrysin gave inhibition zones of equal size to 5 μg streptomycin against Candida albicans and Pseudomonas aeruginosa. The inhibitory activity of lapachol from O. indicum root against soya 5-lipoxygenase (IC(50) 0.79 μg/ml) was equivalent to that of the positive control fisetin (IC(50) 0.97 μg/ml) and 50 μg/ml of the dichloromethane extract of the rootbark gave 100% inhibition of leukocyte lipoxygenase. These activities might indicate an antiinflammatory effect for the dichloromethane extract, mainly due to the lapachol content.
Atrovirinone inhibits proinflammatory mediator synthesis through disruption of NF-kappaB nuclear translocation and MAPK phosphorylation in the murine monocytic macrophage RAW 264.7

Israf DA, Tham CL, Syahida A, Lajis NH, Sulaiman MR, Mohamad AS, et al.

Phytomedicine, 2010 Aug;17(10):732-9.
PMID: 20378317 DOI: 10.1016/j.phymed.2010.02.006

In a previous communication we showed that atrovirinone, a 1,4-benzoquinone isolated from the roots of Garcinia atroviridis, was able to inhibit several major proinflammatory mediators of inflammation. In this report we show that atrovirinone inhibits NO and PGE(2) synthesis through inhibition of iNOS and COX-2 expression. We also show that atrovirinone inhibits the secretion of IL-1beta and IL-6 in a dose dependent fashion whereas the secretion of IL-10, the anti-inflammatory cytokine, was enhanced. Subsequently we determined that the inhibition of proinflammatory cytokine synthesis and inducible enzyme expression was due to a dose-dependent inhibition of phosphorylation of p38 and ERK1/2. We also showed that atrovirinone prevented phosphorylation of I-kappaBalpha, which resulted in a reduction of p65NF-kappaB nuclear translocation as demonstrated by expression analysis. We conclude that atrovirinone is a potential anti-inflammatory drug lead that targets both the MAPK and NF-kappaB pathway.
Barrier protective effect of asiatic acid in TNF-α-induced activation of human aortic endothelial cells

Fong LY, Ng CT, Cheok ZL, Mohd Moklas MA, Hakim MN, Ahmad Z

Phytomedicine, 2016 Feb 15;23(2):191-9.
PMID: 26926181 DOI: 10.1016/j.phymed.2015.11.019

Endothelial cell activation is characterized by increased endothelial permeability and increased expression of cell adhesion molecules (CAMs). This allows monocyte adherence and migration across the endothelium to occur and thereby initiates atherogenesis process. Asiatic acid is a major triterpene isolated from Centella asiatica (L.) Urban and has been shown to possess anti-oxidant, anti-hyperlipidemia and anti-inflammatory activities.
Beneficial effects of natural products on female sexual dysfunction: A systematic review and meta-analysis

Sha'ari N, Woon LS, Sidi H, Das S, Bousman CA, Mohamed Saini S

Phytomedicine, 2021 Dec;93:153760.
PMID: 34638031 DOI: 10.1016/j.phymed.2021.153760

BACKGROUND: Female sexual dysfunction (FSD) includes female orgasmic disorder, female sexual interest or arousal disorder, and genito-pelvic pain or penetration disorder. FSD affects 40% of women worldwide, but it is understudied and likely undertreated. Natural products are frequently used by women to treat FSD, but scientific evidence of their efficacy is lacking.
OBJECTIVE: This systematic review and meta-analysis focused on the study of the efficacy of natural products on FSD.
STUDY DESIGN: Systematic review and meta-analysis of existing studies on natural products in the treatment of FSD.
METHODS: The literature search included MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trial databases for studies published from January 2000 to February 2020. The quality and the level of evidence of the studies were assessed. The association between natural products and FSD was summarized using standardized mean differences (SMD) with a 95% confidence interval (CI).
RESULTS: A total of 536 studies were identified, with 20 of them meeting the criteria. According to this meta-analysis, Tribulus terrestris showed a significant positive effect in improving overall female sexual function (SMD = 1.12, 95% CI = 0.46 - 1.79, p = 0.001) and individual sexual arousal (SMD = 1.03, 95% CI = 0.22 - 1.84, p = 0.013), sexual desire (SMD = 1.08, 95% CI = 0.52 - 1.63, p ≤ 0.001) and sexual orgasm (SMD = 0.51, 95% CI = 0.02 - 1.00, p = 0.040) domains compared to placebo. Panax ginseng was found to be effective in treating sexual arousal (SMD = 0.54, 95% CI = 0.11 - 0.97, p = 0.014) and sexual desire (SMD = 0.59, 95% CI = 0.27 - 0.90, p < 0.001) compared to placebo. Meanwhile, other natural products reviewed in this study, such as Trifolium pretense, did not differ significantly from placebo in terms of improving FSD.
CONCLUSION: Preliminary evidence suggests that Tribulus terrestris and Panax ginseng may be effective as alternative treatments for FSD in a clinical setting.
Berberine and musculoskeletal disorders: The therapeutic potential and underlying molecular mechanisms

Wong SK, Chin KY, Ima-Nirwana S

Phytomedicine, 2020 Jul 15;73:152892.
PMID: 30902523 DOI: 10.1016/j.phymed.2019.152892

BACKGROUND: Musculoskeletal disorders are a group of disorders that affect the joints, bones, and muscles, causing long-term disability. Berberine, an isoquinoline alkaloid, has been previously established to exhibit beneficial properties in preventing various diseases, including musculoskeletal disorders.
PURPOSE: This review article aims to recapitulate the therapeutic potential of berberine and its mechanism of action in treating musculoskeletal disorders.
METHODS: A wide range of literature illustrating the effects of berberine in ameliorating musculoskeletal disorders was retrieved from online electronic databases (PubMed and Medline) and reviewed.
RESULTS: Berberine may potentially retard the progression of osteoporosis, osteoarthritis and rheumatoid arthritis. Limited studies reported the effects of berberine in suppressing the proliferation of osteosarcoma cells. These beneficial properties of berberine are mediated in part through its ability to target multiple signaling pathways, including PKA, p38 MAPK, Wnt/β-catenin, AMPK, RANK/RANKL/OPG, PI3K/Akt, NFAT, NF-κB, Hedgehog, and oxidative stress signaling. In addition, berberine exhibited anti-apoptotic, anti-inflammatory, and immunosuppressive properties.
CONCLUSION: The current evidence indicates that berberine may be effective in preventing musculoskeletal disorders. However, findings from in vitro and in vivo investigations await further validation from human clinical trial.
Bioassay-guided isolation of a sesquiterpene lactone of deoxyelephantopin from Elephantopus scaber Linn. active on Trypanosome brucei rhodesience

Zahari Z, Jani NA, Amanah A, Latif MN, Majid MI, Adenan MI

Phytomedicine, 2014 Feb 15;21(3):282-5.
PMID: 24269185 DOI: 10.1016/j.phymed.2013.09.011

Methanolic extracts of 70 Malaysia plants were screened for their in vitro antitrypanosomal activity using Trypanosome brucei rhodesience, strain STIB 900 and mouse skeletal cell (L-6) in cytotoxicity activity assay. Results indicated that methanol extract from Elephantopus scaber Linn. (E. scaber) possessed the highest value of antitrypanosomal activity with good selectivity index (antitrypanosomal IC50 of 0.22±0.02 μg/ml, SI value of 204.55). Based on these results, E. scaber was chosen for further study by applying bioassay guided fractionation to isolate its antiprotozoal principle. The antiprotozoal principle was isolated from the ethyl acetate partition through solvent fractionation and crystallization process. The isolated active compound 1 was identified as deoxyelephantopin on the basis of its spectral analysis (FTIR, MS, 1D and 2D NMR).
Bioassay-guided isolation of a vasorelaxant active compound from Kaempferia galanga L

Othman R, Ibrahim H, Mohd MA, Mustafa MR, Awang K

Phytomedicine, 2006 Jan;13(1-2):61-6.
PMID: 16360934

Bioassay-guided fractionation was performed on a crude dichloromethane extract of Kaempferia galanga L. using chromatography techniques. Screening of the extract for biological activity started with the brine shrimp lethality bioassay, followed by the study of its antihypertensive activity on anaesthetized rats, which involved monitoring of the extract's effect on mean arterial blood pressure. The components of the fractions obtained from the separation procedures were analyzed using gas chromatography (GC). The yield of the CH(2)Cl(2) extract was 0.29% of the crude plant extract. Analysis of the data for brine shrimp lethality test using the Finney computer program showed that this extract exhibited potent bioactivity with an ED(50) value of 7.92+/-0.13 microgml(-1). Intravenous administration of the extract induced a dose-related reduction of basal mean arterial pressure (MAP) (130+/-5 mmHg) in the anaesthetized rat, with maximal effects seen after 5-10 min of injection. The gas chromatogram showed that the common compound in the active fractions obtained from the bioassay-guided fractionation of the CH(2)Cl(2) extract was ethyl cinnamate. This vasorelaxant active compound, ethyl cinnamate, was isolated as a colorless oil. Ethyl p-methoxycinnamic acid was also isolated as white needles but did not exhibit any relaxant effect on the precontracted thoracic rat aorta.
Biopiracy versus One-World Medicine-From colonial relicts to global collaborative concepts

Efferth T, Banerjee M, Abu-Darwish MS, Abdelfatah S, Böckers M, Bhakta-Guha D, et al.

Phytomedicine, 2019 Feb;53:319-331.
PMID: 30190231 DOI: 10.1016/j.phymed.2018.06.007

BACKGROUND: Practices of biopiracy to use genetic resources and indigenous knowledge by Western companies without benefit-sharing of those, who generated the traditional knowledge, can be understood as form of neocolonialism.
HYPOTHESIS: The One-World Medicine concept attempts to merge the best of traditional medicine from developing countries and conventional Western medicine for the sake of patients around the globe.
STUDY DESIGN: Based on literature searches in several databases, a concept paper has been written. Legislative initiatives of the United Nations culminated in the Nagoya protocol aim to protect traditional knowledge and regulate benefit-sharing with indigenous communities. The European community adopted the Nagoya protocol, and the corresponding regulations will be implemented into national legislation among the member states. Despite pleasing progress, infrastructural problems of the health care systems in developing countries still remain. Current approaches to secure primary health care offer only fragmentary solutions at best. Conventional medicine from industrialized countries cannot be afforded by the impoverished population in the Third World. Confronted with exploding costs, even health systems in Western countries are endangered to burst. Complementary and alternative medicine (CAM) is popular among the general public in industrialized countries, although the efficacy is not sufficiently proven according to the standards of evidence-based medicine. CAM is often available without prescription as over-the-counter products with non-calculated risks concerning erroneous self-medication and safety/toxicity issues. The concept of integrative medicine attempts to combine holistic CAM approaches with evidence-based principles of conventional medicine.
CONCLUSION: To realize the concept of One-World Medicine, a number of standards have to be set to assure safety, efficacy and applicability of traditional medicine, e.g. sustainable production and quality control of herbal products, performance of placebo-controlled, double-blind, randomized clinical trials, phytovigilance, as well as education of health professionals and patients.
Bronchodilator effects of Lignosus rhinocerotis extract on rat isolated airways is linked to the blockage of calcium entry

Lee MK, Lim KH, Millns P, Mohankumar SK, Ng ST, Tan CS, et al.

Phytomedicine, 2018 Mar 15;42:172-179.
PMID: 29655683 DOI: 10.1016/j.phymed.2018.03.025

BACKGROUND: Lignosus rhinocerotis (Cooke) Ryvarden is a popular medicinal mushroom used for centuries in Southeast Asia to treat asthma and chronic cough. The present study aimed to investigate the effect of this mushroom on airways patency.
MATERIALS AND METHODS: The composition of L. rhinocerotis TM02 cultivar was analyzed. Organ bath experiment was employed to study the bronchodilator effect of Lignosus rhinocerotis cold water extract (CWE) on rat isolated airways. Trachea and bronchus were removed from male Sprague-Dawley rats, cut into rings of 2 mm, pre-contracted with carbachol before adding CWE into the bath in increasing concentrations. To investigate the influence of incubation time, tissues were exposed to intervals of 5, 15 and 30 min between CWE concentrations after pre-contraction with carbachol in subsequent protocol. Next, tissues were pre-incubated with CWE before the addition of different contractile agents, carbachol and 5-hydroxytrptamine (5-HT). The bronchodilator effect of CWE was compared with salmeterol and ipratropium. In order to uncover the mechanism of action of CWE, the role of beta-adrenoceptor, potassium and calcium channels was investigated.
RESULTS: Composition analysis of TM02 cultivar revealed the presence of β-glucans and derivatives of adenosine. The extract fully relaxed the trachea at 3.75 mg/ml (p 
Cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and by stimulating insulin secretion in vitro

Hafizur RM, Hameed A, Shukrana M, Raza SA, Chishti S, Kabir N, et al.

Phytomedicine, 2015 Feb 15;22(2):297-300.
PMID: 25765836 DOI: 10.1016/j.phymed.2015.01.003

Although the anti-diabetic activity of cinnamic acid, a pure compound from cinnamon, has been reported but its mechanism(s) is not yet clear. The present study was designed to explore the possible mechanism(s) of anti-diabetic activity of cinnamic acid in in vitro and in vivo non-obese type 2 diabetic rats. Non-obese type 2 diabetes was developed by injecting 90 mg/kg streptozotocin in 2-day-old Wistar pups. Cinnamic acid and cinnamaldehyde were administered orally to diabetic rats for assessing acute blood glucose lowering effect and improvement of glucose tolerance. Additionally, insulin secretory activity of cinnamic acid and cinnamaldehyde was evaluated in isolated mice islets. Cinnamic acid, but not cinnamaldehyde, decreased blood glucose levels in diabetic rats in a time- and dose-dependent manner. Oral administration of cinnamic acid with 5 and 10 mg/kg doses to diabetic rats improved glucose tolerance in a dose-dependent manner. The improvement by 10 mg/kg cinnamic acid was comparable to that of standard drug glibenclamide (5 mg/kg). Further in vitro studies showed that cinnamaldehyde has little or no effect on glucose-stimulated insulin secretion; however, cinnamic acid significantly enhanced glucose-stimulated insulin secretion in isolated islets. In conclusion, it can be said that cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and stimulating insulin secretion in vitro.
Cleistopholine isolated from Enicosanthellum pulchrum exhibits apoptogenic properties in human ovarian cancer cells

Nordin N, Majid NA, Mohan S, Dehghan F, Karimian H, Rahman MA, et al.

Phytomedicine, 2016 Apr 15;23(4):406-16.
PMID: 27002411 DOI: 10.1016/j.phymed.2016.02.016

Cleistopholine is a natural alkaloid present in plants with numerous biological activities. However, cleistopholine has yet to be isolated using modern techniques and the mechanism by which this alkaloid induces apoptosis in cancer cells remains to be elucidated.
Combination of essential oils and antibiotics reduce antibiotic resistance in plasmid-conferred multidrug resistant bacteria

Yap PS, Lim SH, Hu CP, Yiap BC

Phytomedicine, 2013 Jun 15;20(8-9):710-3.
PMID: 23537749 DOI: 10.1016/j.phymed.2013.02.013

In this study we investigated the relationship between several selected commercially available essential oils and beta-lactam antibiotics on their antibacterial effect against multidrug resistant bacteria. The antibacterial activity of essential oils and antibiotics was assessed using broth microdilution. The combined effects between essential oils of cinnamon bark, lavender, marjoram, tea tree, peppermint and ampicillin, piperacillin, cefazolin, cefuroxime, carbenicillin, ceftazidime, meropenem, were evaluated by means of the checkerboard method against beta-lactamase-producing Escherichia coli. In the latter assays, fractional inhibitory concentration (FIC) values were calculated to characterize interaction between the combinations. Substantial susceptibility of the bacteria toward natural antibiotics and a considerable reduction in the minimum inhibitory concentrations (MIC) of the antibiotics were noted in some paired combinations of antibiotics and essential oils. Out of 35 antibiotic-essential oil pairs tested, four of them showed synergistic effect (FIC≤0.5) and 31 pairs showed no interaction (FIC>0.5-4.0). The preliminary results obtained highlighted the occurrence of a pronounced synergistic relationship between piperacillin/cinnamon bark oil, piperacillin/lavender oil, piperacillin/peppermint oil as well as meropenem/peppermint oil against two of the three bacteria under study with a FIC index in the range 0.26-0.5. The finding highlighted the potential of peppermint, cinnamon bark and lavender essential oils being as antibiotic resistance modifying agent. Reduced usage of antibiotics could be employed as a treatment strategy to decrease the adverse effects and possibly to reverse the beta-lactam antibiotic resistance.
Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells

Lee HM, Patel V, Shyur LF, Lee WL

Phytomedicine, 2016 Nov 15;23(12):1535-1544.
PMID: 27765374 DOI: 10.1016/j.phymed.2016.09.005

BACKGROUND: Oral cancer is the sixth most common cancer worldwide and 90% of oral malignancies are caused by oral squamous cell carcinoma (OSCC). Curcumin, a phytocompound derived from turmeric (Curcuma longa) was observed to have anti-cancer activity which can be developed as an alternative treatment option for OSCC. However, OSCC cells with various clinical-pathological features respond differentially to curcumin treatment.
HYPOTHESIS: Intracellular copper levels have been reported to correlate with tumor pathogenesis and affect the sensitivity of cancer cells to cytotoxic chemotherapy. We hypothesized that intracellular copper levels may affect the sensitivity of oral cancer cells to curcumin.
METHODS: We analysed the correlation between intracellular copper levels and response to curcumin treatment in a panel of OSCC cell lines derived from oral cancer patients. Exogenous copper was supplemented in curcumin insensitive cell lines to observe the effect of copper on curcumin-mediated inhibition of cell viability and migration, as well as induction of oxidative stress and apoptosis. Protein markers of cell migration and oxidative stress were also analysed using Western blotting.
RESULTS: Concentrations of curcumin which inhibited 50% OSCC cell viability (IC50) was reduced up to 5 times in the presence of 250 µM copper. Increased copper level in curcumin-treated OSCC cells was accompanied by the induction of intracellular ROS and increased level of Nrf2 which regulates oxidative stress responses in cells. Supplemental copper also inhibited migration of curcumin-treated cells with enhanced level of E-cadherin and decreased vimentin, indications of suppressed epithelial-mesenchymal transition. Early apoptosis was observed in combined treatment but not in treatment with curcumin or copper alone.
CONCLUSION: Supplement of copper significantly enhanced the inhibitory effect of curcumin treatment on migration and viability of oral cancer cells. Together, these findings provide molecular insight into the role of copper in overcoming insensitivity of oral cancer cells to curcumin treatment, suggesting a new strategy for cancer therapy.
Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells

Saeed MEM, Boulos JC, Elhaboub G, Rigano D, Saab A, Loizzo MR, et al.

Phytomedicine, 2019 Sep;62:152945.
PMID: 31132750 DOI: 10.1016/j.phymed.2019.152945

BACKGROUND: Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad.
PURPOSE: This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR).
METHODS: Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK).
RESULTS: Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins.
CONCLUSION: CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.

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