Literature DB >> 27086008

Screening of promising chemotherapeutic candidates from plants extracts.

Junei Kinjo1, Daisuke Nakano2, Toshihiro Fujioka2, Hikaru Okabe2.   

Abstract

Over the course of our studies investigating anti-proliferative properties of compounds originating from plants against human gastric adenocarcinoma (MK-1), human uterine carcinoma (HeLa), murine melanoma (B16F10), and two human T cell lymphotropic virus type 1 (HTLV-1)-infected T-cell lines (MT-1 and MT-2), we have screened 582 extracted samples obtained from a variety of parts from 370 plants. A few extracts showed anti-proliferative activity against all cell lines, but upon further investigation, toxicity toward selected cell lines was recognized. After activity-guided fractionation, isolation of the active principles was achieved. Structure-activity relationship studies identified the components and functionalities responsible for the specific selectivity against each cancer cell line. The effect of polyacetylenes against MK-1 cells was more potent than against HeLa and B16F10 cells. The compound having a 3,4-dihydroxyphenethyl group also showed an anti-proliferative effect against B16F10 cells. Some 6-methoxyflavone derivatives and 8-hydroxy furanocoumarins were good inhibitors of HeLa cell growth. The 17 compounds whose EC50 values were less than 1 nM did not show specific cellular selectivity. Because the cytotoxic effect of 24, 25-dihydrowithanolide D toward control cells was observed at a concentration about 100 times higher than those for the cancer cell lines, withanolide was identified as the most promising chemotherapeutic candidate in our experiments.

Entities:  

Keywords:  Active principles; Activity-guided fractionation; Anti-proliferative activity; Cancer cell lines; Plant extracts; Structure–activity relationship

Mesh：

Substances：

Year:  2016        PMID： 27086008      PMCID： PMC4935755          DOI： 10.1007/s11418-016-0992-2

Source DB:  PubMed          Journal:  J Nat Med        ISSN： 1340-3443            Impact factor:   2.343


Introduction

Development of anti-neoplastic drugs is the focus of numerous research programs around the world. Plants are the richest source of novel chemical compounds and in fact, many natural product-derived compounds have been identified as chemotherapeutic candidates [1]. For instance, vinca alkaloids, podophyllotoxins, taxanes, and camptothecins are four main classes of compounds that are well-known anti-neoplastic drugs originating from plants [2]. It is significant that over 60 % of the currently used anti-neoplastic drugs are derived from natural sources including plants [3]. Over the course of our studies investigating the anti-proliferative characteristics of compounds originating from plants against human gastric adenocarcinoma (MK-1), human uterine carcinoma (HeLa), murine melanoma (B16F10), and two human T-cell lymphotropic virus type 1 (HTLV-1)-infected T-cell lines (MT-1 and MT-2), we have already reported many compounds active against cancer cell lines [4]. Herein, we report not only the screening results against the above cell lines but also the active principles and analysis of their structure–activity relationships.

Screening results

The 582 samples obtained from a variety of plant parts from 370 plants (302 genera, 104 families) were extracted with MeOH under reflux. The anti-proliferative effects of the extracts against the MK-1, HeLa, B16F10, MT-1, and MT-2 cell lines were evaluated (Table 1). The extracts listed in Table 1 are classified in the Angiosperm Phylogeny Group III system. The extracts of the leaves of Annona squamosa (Annonaceae), the aerial parts and roots of Tylophora tanakae (Asclepiadaceae), and the leaves of Thuja occidentalis (Cupressaceae) showed the most potent anti-proliferative activities against all cell lines. The extracts of the leaves of Annona cherimola (Annonaceae), the fresh leaves of Tylophora ovata and T. ovata var. brownii (Asclepiadaceae), twigs of T. ovata, the roots of Saussurea lappa (Asteraceae), the seeds of Luffa acutangula (Cucurbitaceae), the leaves of Juniperus rigida (Cupressaceae), the woods of Haematoxylum brasileto (Fabaceae), the rhizomes of Coptis japonica (Ranunculaceae), the roots of Ruta graveolens (Rutaceae), and the leaves of Cephalotaxus harringtonia (Taxaceae) showed decreasing levels of potency in the order listed. Homoharringtonine (Omacetaxine), a protein translation inhibitor for the treatment of chronic myelogenous leukemia, is found in the leaves of C. harringtonia [5]; therefore, the extract might show potent activity. There were a few extracts that had anti-proliferative activity against all cell lines and upon further investigation, toxicity toward selected cell lines was identified.
Table 1

Anti-proliferative activities of the plants extracts against MK-1, HeLa, B16F10, MT-1, and MT-2 cells

FamilyScientific namePartsMK-1HeLaB16F10MT-1MT-2
Acanthaceae Dicliptera japonica Aerial parts−−+−−
Justicia procumbens Whole part−++******
Actinidiaceae Actinidia chinensis Fruits++++++−−
Adoxaceae Sambucus chinensis Leaves−−−−−
Stems−−−−−
Aizoaceae Tetragonia expansa Whole part−−+−−
Amaranthaceae Achyranthes fauriei Roots+++++++−−−
Celosia argentea Seeds−−−−−
Chenopodium ambrosidoides Aerial parts−−−−−
Chenopodium ambrosidoides var. anthelminticum Leaves+−+−−
Stems−−−NTNT
Chenopodium graveolens Aerial parts++++−**
Gomphrena globosa Whole part−−−−−
Amaryllidaceae Allium sativum var. pekinense Bulbs++++++++−−
Anacardiaceae Mangifera indica Barks++++++++++++++++++−−
Leaves++++++**−
Peels+++****
Pulp−−−−−
Seeds++++++++****
Annonaceae Annona cherimola Barks+−+********
Leaves++++++++++++++++++****
Annona muricata Leaves++++++++++−−
Stems++++++++++++**−
Annona reticulata Barks+−−−−
heartwoods+−−NTNT
Leaves+++++****************
Annona squamosa Leaves+++++++++++++++++************
Twigs+++++++++++++**−
Apiaceae Angelica acutiloba Fruits+−−NTNT
Leaves−−−NTNT
Roots−−−−−
Angelica dahurica Fruits++−+****
Angelica decursiva Aerial parts−−−−−
Leaves++−−NTNT
Fruits+−+++****
Roots+−−****
Angelica japonica Fruits++−++NTNT
Leaves−−−NTNT
Roots+++−−NTNT
Angelica keiskei Aerial parts−−+−−
Leaves−−−NTNT
Fruits−−+−−
Roots+−++****
Angelica kiusiana Leaves−−+−−
Angelica pubescens Roots+++−−
Anethum graveolens Fruits−−−NTNT
Leaves−−+NTNT
Roots+++−−NTNT
Anthriscus cerefolium Fruits++−−NTNT
Anthriscus sylvestris Fruits++++++++++++++++++NTNT
Leaves++++++++++++++++++NTNT
Roots++++++++++++++++++NTNT
Bupleurum falcatum Leaves−−−NTNT
Bupleurum rotundifolium Fruits++++++++++NTNT
Carum carvi Fruits++−+NTNT
Leaves+−−NTNT
Roots++++−+NTNT
Centella asiatica Leaves++−++NTNT
Aerial parts+−+++−−
Cnidium monnieri Fruits+++++++−−
Cnidium officinale Leaves−−−NTNT
Rhizomes−−+−−
Coriandrum sativum Leaves−−−−−
Fruits++−++NTNT
Cryptotaenia japonica Leaves++−+NTNT
Foeniculum vulgare Leaves+−+NTNT
Glehnia littoralis Fruits+++++−+++NTNT
Heracleum moellendorffii Leaves+−−NTNT
Roots+++−−NTNT
Osmorhiza aristata Aerial parts−−++++++−−
Roots−−−****
Peucedanum japonicum Leaves−−−−−
Stems, Root barks++−****
Woods−−−−−
Peucedanum praeruptorum Roots−−−****
Torilis japonica Fruits++++−++++NTNT
Leaves−−−NTNT
Roots+++−+NTNT
Apocynaceae Apocynum venetum Whole part+−+−−
Cerbera manghas BarksNTNTNT****
Leaves+++++++−********
Trachelospermum jasminoides Aerial parts−−−****
Trachelospermum liukiuense Aerial parts−−+−**
Aquifoliaceae Ilex cornuta Fruits−−+−−
Leaves+−+******
Ilex kudingcha LeavesNTNTNT−−
Ilex latifolia Leaves−−+−−
Ilex rotumda Fruits−−−****
Leaves+++****
Araceae Arisaema ringens Tubers+−+−−
Pinellia ternata Tubers−−−−−
Araliaceae Aralia cordata Roots−−−−−
Aralia elata Barks+−++++−−
Leaves+−+−−
Dendropanax trifidus Barks−−+−−
Fruits−−+−−
Leaves+++++−−
Eleutherococcus senticosus Root barks−−+****
Fatsia japonica Barks+−−−−
Leaves+−−−−
Roots+−−−−
Hedera rhombea Fruits−−+−−
Leaves−−+−**
Stems−−+****
Hydrocotyle nepalensis Aerial parts−−+−−
Schefflera arboricola Leaves+++−−
Tetrapanax papyriferum Leaves++++++++**−
Woods+++−−
Araucariaceae Araucaria heterophylla Leaves+++++++++++++++−−
Aristolochiaceae Aristolochia spp.Roots++−********
Asarum nipponicum Aerial parts+−−−−
Roots+−−********
Asarum sieboldii Roots+−+−−
Asclepiadaceae Asclepias curassavica Leaves++++++****
Roots+++++++−******
Stems+++++++−********
Cynanchum caudatum Leaves−−+−−
Marsdenia cundurango Roots−−−−−
Marsdenia tomentosa Leaves−−+−−
Stems−−−−−
Asclepiadaceae Metaplexis japonica Aerial parts−−−NTNT
Roots−−−−−
Periploca spp.Root barks+++++++++****
Tylophora ovata Fresh leaves+++++++++++********
Twigs+++++++++++++++********
Tylophora ovata var. brownii Fresh leaves++++++++++++++++++********
TwigsNTNTNT−−
Tylophora tanakae Aerial parts++++++++++++++++++**********
Roots++++++++++++++++++************
Asparagaceae Anemarrhena asphodeloides Roots, Rhizomes−−−****
Dracaena draco Barks−−+++−−
Leaves−−++++−−
Ophiopogon japonicus Tubers−−−−−
Asteraceae Achillea millefolium Leaves−−+−−
Stems−−+−−
Adenocaulon himalaicum Aerial parts+++−**
Roots−−−−−
Adenostemma lavenia Aerial parts+−+−**
Arctium lappa Roots−−−−−
Seeds+−++−−
Artemisia absinthium Aerial parts+−−****
Leaves−−−−−
Roots+−+****
Stems−−−−−
Artemisia campestris Aerial parts−−−−−
Artemisia capillaris Aerial parts+−+−**
Roots−−−−−
Artemisia ludoviciana var. mexicana Aerial parts+++++++−−
Aster spathulifolius Leaves+−+++****
Stems+−+****
Aster verticillatum Aerial parts+−+−−
Bidens frondosa Aerial parts+++−−
Roots, Rhizomes+++++++++++****
Carthamus tinctorius Flowers−−−−−
Centaurea benedictus Leaves+−+NTNT
Chrysanthemum vulgare Aerial parts+++****
Cichorium intybus Aerial parts+−+−−
Roots+−+−−
Cosmos bipinnatus Seeds−−−−−
Crassocephalum crepidioides Aerial parts−−+−−
Roots, Rhizomes−−+−−
Crepidiastrum lanceolatum Aerial parts−−−−−
Roots++++++++++++++++−−
Eclipta prostrata Whole part+−+−−
Eupatorium stoechadosmum Leaves−−−−−
Roots+++++−−
Stems−−−−−
Euryops pectinatus Leaves−−+−−
Stems−−−−−
Helianthus annuus Aerial parts−−−****
Inula helenium Roots+++++++++NTNT
Ligularia japonica Leaves−−−**−
Roots−−−−−
Neurolaena lobata Leaves−++NTNT
Parasenecio tebakoensis Aerial parts+−+−−
Santolina chamaecyparissus Leaves−−+−−
Stems−−+++−−
Saussurea lappa Roots+++++++++++++++******
Senecio vulgaris Whole part−−−−−
Siegesbeckia glabrescens Leaves++−−−
Roots−−−−−
Sonchus asper Aerial parts−−+−−
Tagetes patula Aerial parts−−+−**
Roots−−+−−
Tridax procumbens Leaves−−−NTNT
Tussilago farfara Roots+−+−−
Wedelia prostrata Whole part−−+****
Xanthium strumarium Fruits−−−−−
Balsaminaceae Impatiens textori Aerial parts−−+****
Berberidaceae Berberis japonica Leaves++++++−**
Roots++++++****
Stems++++++******
Epimedium grandiflorum subsp.Roots, Rhizomes−−−−−
Epimedium sagittatum Aerial parts+++++++++++++−−
Nandina domestica Barks+++++**−
Leaves++−++++−−
Bignoniaceae Pseudocalymma alliaceum Aerial parts−−+**−
Tabebuia spp.Barks+++****
Boraginaceae Lithospermum officinale var. erythrorhizon Roots−−−−−
Brassicaceae Isatis indigotica Fruits−−+****
Leaves−−−−−
Roots−−−−−
Lepidium apetalum Seeds+++++++++−****
Lepidium virginicum Whole part−−+−−
Thlapsi arvense Seeds−−−−−
Burseraceae Bursera simaruba Fruits++++−−
Leaves+++++****
Woods++++NTNT
Campanulaceae Codonopsis spp.Roots−−−−−
Cannabaceae Humulus japonicus Aerial parts−−+****
Caprifoliaceae Lonicera japonica Flowers−−−−−
Leaves+−+−−
Stems−−+−−
Caricaceae Carica papaya Barks−−−−−
Leaves+−+−−
Roots−−−−−
Caryophyllaceae Agrostemma githago Seeds+−+−−
Vaccaria segetalis Seeds+−+−−
Celastraceae Celastrus orbiculatus Vines−−−−−
Euonymus alatus Barks−−+++NTNT
Euonymus japonicus Barks++++++++****
Leaves−−++−−
Maytenus diversifolia Leaves−−+−−
Stems+++++++++NTNT
Chloranthaceae Sarcandra glabra Roots−++++−−
Clusiaceae Garcinia subelliptica Barks++++++++−−
Heartwoods−−−−−
Leaves+−+−−
Garcinia xanthochymus Leaves−+−NTNT
Pulp+−−−−
Seeds++−****
Stems+++NTNT
Combretaceae Terminalia chebula Fruits++++++++****
Commelinaceae Commelina communis Whole part−−+−−
Cornaceae Camptotheca acuminata Fruits+++++++++++++****
Cornus officinalis Fruits−−−−−
Crassulaceae Bryophyllum pinnatum Aerial parts+−+−−
Roots+++++++++++******
Hylotelephium erythrosticum Roots++++−−
Orostachys japonicus Whole part−−+−−
Sedum aizoon var. floribundum Roots+++++++−−
Sedum tomentosum Whole part−−+−−
Cucurbitaceae Actinostemma lobatum Aerial parts++−−−
Citrullus colocynthis Seeds−−−−−
Gynostemma pentaphyllum Aerial parts−−−−−
Lagenaria leucantha var. gourda Fruits++++++++++++******
Leaves−−+−−
Roots+++++−−
Seeds++++++++++−−
Stems+++++++−−
Lagenaria leucantha var. microcarpa Fruits+++++++++++++NTNT
Seeds++++++++++++−−
Luffa acutangula Aerial parts+++****
Seeds++++++++++++++******
Luffa aegyptiaca Fruits−−−−−
Momordica charantia Aerial parts−−−−−
Fruits−−−NTNT
Roots−−−−−
Momordica cochinchinensis Seeds++++++++++++++++++−−
Sicana odorifera Fruits++−NTNT
Trichosanthes kirilowii var. japonica Roots++++++++−−
Cupressaceae Biota orientalis Leaves+++++++++****
Stems+++−−
Juniperus chinensis var. kaizuka Hort.Leaves++++++****
Stems+++******
Juniperus rigida Leaves+++++++++++++++++********
Stems+++++++++**−
Thuja occidentalis Leaves++++++++++++++++++************
Stems++++++++********
Cycadaceae Cycas revoluta Leaves−−+−−
Peels−−+−−
Seed kernels−−−−−
Daphniphyllaceae Daphniphyllum macropodum Barks−+−−−
Leaves−−+−−
Elaeocarpaceae Elaeocarpus sylvestris var. ellipticus Barks++++++++++****
Leaves++++++++−**
Eucommiaceae Eucommia ulmoides Barks−−−****
Euphorbiaceae Acalypha australis Roots++++−−
Croton spp.Leaves+−+−−
Euphorbia helioscopia Aerial parts−++****
Roots−−+−**
Euphorbia jolkini Aerial parts+++++++−−
Roots+++++++−−
Euphorbia supina Whole part+++++−−
Euphorbia tirucalli Aerial parts++++−−
Hura polyandra Seeds+++−−−−
Fabaceae Acacia melanoxylon Barks+++++++−−
Leaves+++−**
Apios americana FlowersNTNTNT−−
Astragalus membranaceus Roots−+−−−
Canavalia gladiata Roots−+−−**
Seeds−−+****
Cassia obtusifolia Seeds−++−−
Crotalaria juncea Leaves+−+−**
Seeds−−−−−
Stems−−+−−
Erythrina variegata var. orientalis Barks−+−−−
Euchresta japonica Roots−+−−**
Eysenhardtia polystachia Woods+++++−−
Gliricidia sepium Leaves+−++−−
Glycyrrhiza pallidiflora Underground parts−+−−−
Glycyrrhiza uralensis Roots−+−−−
Haematoxylum brasileto Woods+++++++++++********
Lonchocarpus oxacensis Roots+−−NTNT
Lonchocarpus unifoliolatus Roots+−−NTNT
Medicago polymorpha Whole part−−−−−
Melilotus officinalis Whole part−+−−−
Psoralea corylifolia Seeds++++++−**
Rhynchosia volubilis Seeds+++++++++**−
Sophora japonica Fruits−−+****
Trifolium dubium Aerial parts−+−−−
Zornia spp.Leaves+−+−**
Gelsemiaceae Gelsemium sempervirens Leaves−−+++−−
Stems−−+−−
Geraniaceae Pelargonium graveolens Leaves++++++++−**
Stems++++++++−**
Iridaceae Crocosmia aurea Bulbs−−−−−
Jugulandaceae Juglans mandshurica var. sachalinensis Barks+++++++−−
Lamiaceae Ajuga decumbens Whole part−−−−−
Ajuga reptans Leaves−−−−−
Roots−−−−−
Caryopteris incana Aerial parts−−+−−
Clerodendron thomsonaiae Leaves−−−NTNT
Clerodendrum bungei Flowers−−−−−
Leaves−−++−−
Stems−−−−−
Clerodendrum trichotomum Barks+−+++−−
Flowers−−−−−
Fruits−−+−−
Leaves+−+++−−
Elsholtzia ciliata Aerial parts+−+−−
Glechoma longituba Whole part−−−−−
Isodon japonicus Leaves++++++−−
Roots+++−−
Stems++++++−−
Lamium amplexicaule Whole part−−−−−
Leonurus sibiricus Aerial parts−−−****
Roots−−+−−
Seeds−−+−−
Rosmarinus officinalis Leaves++++++++****
Salvia miltiorrhiza Roots+−+−−
Scutellaria baicalensis Roots+++−−
Scutellaria barbata Whole part−−+****
Teucrium japonicum Leaves−−+++−−
Vitex trifolia BranchesNTNTNT−−
LeavesNTNTNT−−
Lauraceae Cinnamomum cassia Barks+++****
Lindera strychnifolia Roots+++−−
Persea americana Leaves+++++++++++++++++−−
Pulp+++++−−
Seeds+++−−
Twigs+++−−
Liliaceae Fritillaria verticillata var. thungergii Bulbs−−+−−
Lythraceae Cuphea hyssopifolia Aerial parts++++−−
Roots++++−−
Punica granatum Peels++++++++****
Magnoliaceae Magnolia ovata Barks+++−−
Malvaceae Abelmoschus manihot Leaves−++−−
Althaea cannabina Leaves−−−−−
Chorisia speciosa Immatured fruits−−−−−
Corchoropsis tomentosa Fruits−−+****
Leaves+++++−−
Stems−−+−−
Gossypium arboreum Leaves++++−−
Roots++++−−
Stems+−+−−
Gossypium brasiliensis Leaves++++++−−
Roots−++−−
Stems−++−−
Malvaviscus arboreus Leaves+−−−−
Pachira macrocarpa Barks+++****
Leaves+−+−**
Sterculia nobilis Barks−−−−−
Heartwoods−−−−−
Leaves++++****
Meliaceae Melia azedarach var. toosendan Fruits−−++++****
Menispermaceae Cocculs trilobus Fruits−−+−−
Leaves+++−−
Vines−−+−−
Stephania tetrandra Roots−−+****
Tinospora tuberculata Stems−−−−−
Moraceae Ficus carica Leaves−−+−−
Ficus pumila Fruits+−+−−
Leaves+++++−−
Stems−−+−−
Morus alba Root barks−−−−−
Myristicaceae Myristica fragrans MeOH−oil++++++NTNT
MeOH−ppt−−+−−
Muntingiaceae Muntingia calabura Fruits+−+NTNT
Leaves++++++−−
Myrtaceae Eugenia javanica Barks++++++++++−−
Leaves+++++−−
Eugenia uniflora Leaves+++++−−
Twigs+++++++−**
Psidium cattleyanum Branches+++++**−
Fruits−−−−−
Leaves+++−−
Psidium guajava Branches+++++−−
Leaves+++−−
Psidium littorale Leaves+++++−−
Twigs++++++++++−**
Nyctaginaceae Mirabilis jalapa Leaves−−+−**
Roots+++−−
Oleaceae Ligustrum japonicum Immatured fruits+−+−−
Leaves+++++NTNT
Ligustrum lucidum Fruits+−+−−
Leaves−−++−−
Ligustrum ovalifolium Leaves−−+−−
Ligustrum purpurascens Leaves+++−−
Ligustrum salicinum Leaves+−+++−−
Orchidaceae Dendrobium spp.Aerial parts+++−−
Orobanchaceae Cistanche deserticola Stems−−+−−
Oxalidaceae Averrhoa carambola Barks−−+−−
Leaves−−+−−
Paeoniaceae Paeonia lactiflora Roots−−−−−
Papaveraceae Corydalis heterocarpa var. japonica Aerial parts−−+****
Roots+−−−−
Corydalis turtschaninovii forma yanhusuo Tubers++++−**
Macleaya cordata Aerial parts+++++++++−−
Underground parts+++****
Phrymaceae Phryma leptostachya Aerial parts+−+−−
Roots+++−−
Phyllanthaceae Phyllanthus aciduse Leafstalks, Twigs−−−−−
Leaves+−−−−
Phyllanthus urinaria Whole parts++++++−−
Phytolaccaceae Petiveria alliacea Leaves+++++NTNT
Phytolacca americana Roots−−−−−
Rivina humilis Aerial parts−−+−−
Piperaceae Piper spp.Leaves+−+****
Pittosporaceae Pittosporum tobira Barks−−−−−
Fruits+++−−
Leaves+−+−−
Peels+++****
Plantaginaceae Pentstemon gloxinioides Leaves−−+−−
Rhizomes−−+++−−
Stems−−+−−
Picrorhiza scrophulariiflora Rhizomes−−+−−
Russelia equisetiformis Aerial parts+−++++−−
Plumbaginaceae Plumbago capensis Whole part+++−−
Podocarpaceae Podocarpus macrophyllus Leaves+++++−−
Stems++++++−−
Polygalaceae Polygala tenuifolia Roots−−−−−
Polygonaceae Fallopia japonica Roots+++−−
Polygonum orientale Seeds+++++−−
Polygonum tinctorium Whole part−−−****
Rheum palmatum Rhizomes++++++++−−
Rumex acetosa Roots, Rhizomes−−+****
Rumex japonicus Roots, Rhizomes−−++−**
Polypodiaceae Drynaria fortunei Rhizomes−−+−−
Phleboidum aureum Dried roots+−+−−
Fresh roots+−−−**
Whole part+−+−−
Portulacaceae Portulaca oleracea Whole part+−+−**
Primulaceae Ardisia crenata Leaves−−+++−−
Roots++++++++********
Stems−−+++−−
Ardisia japonica Leaves+++−−
Stems, Undergorund parts+++++−−
Lysimachia japonbica Whole part−−+−−
Proteaceae Macadamia ternifolia Leaves+++++−−
Twigs++++++++NTNT
Pteridaceae Pteris multifida Aerial parts−−−−−
Roots, Rhizomes+++−−
Ranunculaceae Cimicifuga simplex var. ramosa Aerial parts−−+−−
Underground parts−−+−−
Clematis paniculata Aerial parts+−+−−
Coptis japonica Rhizomes++++++++++++++++****
Thalictrum thunbergii Aerial parts−−+−−
Underground parts−−+++−−
Rhamnaceae Berchemia racemosa Leaves−−+−−
Stems−−+−−
Hovenia dulcis Fruits−−+−−
Zizyphus jujube var. jujuba Fruits−−−−−
Zizyphus jujube var. spinosa Seeds++−+−−
Rehmanniaceae Rehmannia glutinosa var. purpurea Roots−−−−−
Rosaceae Agrimonia pilosa Whole part−−++−−
Chaenomeles sinensis Fruits+++++−−
Crataegus cuneata Fruits−+−−−
Eryobotrya japonica Barks+++−−
Leaves−−+−−
Seeds−+−−−
Geum japonicum Aerial parts+++−−
Roots+++++−−
Potentilla chrysantha Whole part−−+−−
Potentilla fragarioides var. major Aerial parts−−+−−
Underground parts+++++****
Potentilla indica Whole part+−+−−
Prunus armeniaca Seeds kernels−+−−−
Rosa multiflora Fruits−−+−−
Rubus hirsutus Aerial parts−−+−−
Roots+−+−−
Sanguisorba officinalis var. carnea Roots++++++++−−
Rubiaceae Damnacanthus macrophyllus var. macrophyllus Leaves−++++−−
Roots−−−−−
Stems−−−−−
Galium pogonanthum Aerial part−−+−**
Hamelia patens Leaves, Twigs+−++−−
Hedyotis diffusa Whole part−−−−−
Paederia scandens Fruits++−−−
Leaves−−−−−
Stems−−−−−
Rubia argyi Roots++++++++++++****
Uncaria rhynchophylla Hooks−−++−−
Rutaceae Boenninghausenia japonica Aerial parts+++++****
Roots++++++++********
Citrus grandis Peels−−+−−
Citrus natsudaidai Immatured fruits−−−−−
Evodia rutaecarpa Barks−−+−−
Fruits++++++++++−−
Orixa japonica Leaves+++−−
Stems−−+−−
Phellodendron amurense Barks++++++++******
Ruta graveolens Aerial parts−+++++****
Leaves+++******
Roots++++++++++++******
Zanthoxylum ailanthoides Barks+++++****
Fruits−−+**−
Leaves−−+****
Woods−−+−**
Zanthoxylum bungeanum Peels−−+****
Sapindaceae Aesculus turbinata Seeds++−−−−
Cardiospermum halicacabum Seeds−−+−−
Dimocarpus longan Leaves+++++++−−
Twigs+++++++−−
Litchi chinensis Leaves+++++−−
Twigs+++++−−
Sapindus mukurossi Peels+++++++++******
Seeds−−+−−
Sapotaceae Chrysophyllum cainito Leaves+++NTNT
Pouteria sapota Seeds+−−−−
Schisandraceae Kadsura japonica Leaves−−+−−
Vines+−+−**
Schisandra chinensis Fruits−−−−−
Scrophlariaceae Scrophularia buergeriana Roots−−−−−
Verbascum thapsus Leaves−−+−−
Simaroubaceae Picrasma quassioides Woods+++−−
Smilacaceae Smilax china Rhizomes+++++−−
Smilax medica Rhizomes+++−−
Solanaceae Brunfelsia latifolia Leaves+−+−−
Nicandra physalodes Fruits−−−−−
Leaves+−+++−−
Roots+++−+++−−
Stems−−−−−
Physalis angulata Aerial parts++++++++++−−
Roots−−−−−
Physalis pruinosa Aerial parts++++++++++++****
Roots+++++++++++********
Solanum mammosum Aerial parts+−+−−
Roots+−−−−
Solanum nigrum Aerial parts−−+**−
Fruits+++**−
Roots+++++****
Taxaceae Cephalotaxus harringtonia Leaves++++++++++++********
Stems, Twigs++++++++++++++−−
Torreya grandis Seeds++++++−−
Theaceae Camellia sinensis Leaves++NTNTNTNT
Thymelaeaceae Daphne genkwa Flowers+++****
Daphne odora Roots−−++++−−
Edgeworthia chrysantha Roots−−+−−
Urticaceae Cecropia obtusifolia Fresh leaves+−+−−
Leaves++++−−
Urtica dioica Leaves, Twigs−−−−−
Urtica thunbergiana Aerial parts−−+−−
Verbenaceae Aloysia triphylla Leaves+++++−−
Lantana camara var. aculeata Leaves+++++++−−
Stems+++++++−−
Lantana montevidensis Leaves++++++++++++++−−
Lippia canescens Aerial parts−−+−−
Lippia dulcis Aerial parts+−++++−−
Lippia triphylla Leaves+−+++−−
Stems−−+−−
Verbena brasiliensis Aerial parts+−+−−
Roots+−++−−
Verbena officinalis Aerial parts+−+−−
Roots−−−−−
Vitaceae Cayratia japonica Aerial parts−−+−−
Xanthorrhoeaceae Aloe ferox Leaves+−−−−
Zingiberaceae Alpinia japonica Fruits−−−−−
Seeds−++−**
Curcuma zedoaria Rhizomes+−+****
Hedychium coronarium Rhizomes+++****
Zingiber officinale Rhizomes++++******

The extracts are classified in the Angiosperm Phylogeny Group III system. EC50 values against MK-1, HeLa, and B16F10 cells (<3.13 μg/mL, ++++++; 3.13–6.25 μg/mL, +++++; 6.25–12.5 μg/mL, ++++; 12.5–25 μg/mL, +++; 25–50 μg/mL, ++; 50–100 μg/mL, +; >100 μg/mL, -). EC50 values against MT-1 and MT-2 cells (<0.1 μg/mL, ********; 0.1–1 μg/mL, ******; 1–10 μg/mL, ****; 10–100 μg/mL, **; >100 µg/mL, -)

NT not tested

Anti-proliferative activities of the plants extracts against MK-1, HeLa, B16F10, MT-1, and MT-2 cells The extracts are classified in the Angiosperm Phylogeny Group III system. EC50 values against MK-1, HeLa, and B16F10 cells (<3.13 μg/mL, ++++++; 3.13–6.25 μg/mL, +++++; 6.25–12.5 μg/mL, ++++; 12.5–25 μg/mL, +++; 25–50 μg/mL, ++; 50–100 μg/mL, +; >100 μg/mL, -). EC50 values against MT-1 and MT-2 cells (<0.1 μg/mL, ********; 0.1–1 μg/mL, ******; 1–10 μg/mL, ****; 10–100 μg/mL, **; >100 µg/mL, -) NT not tested Table 2 shows a summary of the sensitivity of the plant extracts toward MK-1, HeLa, B16F10, MT-1, and MT-2 cells. The percentage of extracts that were active at concentrations of less than 100 μg/mL against the various cell lines were as follows: B16F10 (70 %), MK-1 (55 %), HeLa (39 %), MT-1 (23 %), and MT-2 (28 %). Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T lymphocytes caused by HTLV-1. Although conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to ATL patients, the therapeutic outcomes remain very poor. Therefore, these results suggest that a few plant extracts were sensitive to the T-cell lymphotropic virus type 1 (HTLV-1)-infected T cells (MT-1 and MT-2).
Table 2

Summary of the sensitivity of the plants extracts against MK-1, HeLa, B16F10, MT-1, and MT-2 cells

Confirmed EC50 activitiesMK-1 (%)HeLa (%)B16F10 (%)MT-1 (%)MT-2 (%)
<100 μg/mL5539702328
<12.5 μg/mL7.67.812––
<10 μg/mL–––4.55.3
<3.13 μg/mL1.92.83.6––
<1 μg/mL–––1.10.9

The percentages for each cell type represent the percent of the extracts with EC50s within each category of activity

Summary of the sensitivity of the plants extracts against MK-1, HeLa, B16F10, MT-1, and MT-2 cells The percentages for each cell type represent the percent of the extracts with EC50s within each category of activity

Active principles

Polyacetylenes (Fig. 1)

After activity-guided fractionation against MK-1 cells, two active polyacetylenes, falcarindiol (1) and panaxynol (2), were isolated from the roots of Heracleum moellendorffii (Apiaceae) [6]. Six other polyacetylenes were isolated from the roots of Angelica japonica (Apiaceae) [7] together with 1 and 2 after activity-guided fractionation against MK-1 cells. Among them, four compounds were furanocoumarin ethers of 1. It was evident that the effects of these compounds except for compound 3 against MK-1 cells were more potent than their effects against HeLa and B16F10 cells (Table 3). Because compound 2 showed 16 times greater activity when compared with its 8-hydroxy derivative (1), the presence of a hydroxy group at C-8 was presumed to reduce activity. The most potent compound was panaxynol (2), with an EC50 value of 1.2 μM against MK-1 cells. Bioactive panaxynol-type polyacetylenes in plant-derived foods have attracted attention as health-promoting compounds [8].
Table 3

Anti-proliferative activities of compounds 1–118 (EC50, μM) against MK-1, HeLa, B16F10, MT-1, MT-2, and control PBMNC cells

Compound nameMK-1HeLaB16F10MT-1MT-2Normal
Falcarindiol (1)1514989NTNTNT
Panaxynol (2)1.222480NTNTNT
8-O-Acetylfalcarindiol (3)274175203NTNTNT
(9Z)1,9-Heptadecadiene-4,6-diyne-3,8,1 1-triol (4)810662NTNTNT
Japoangelol A (5)152432NTNTNT
Japoangelol B (6)8.72642NTNTNT
Japoangelol C (7)203228NTNTNT
Japoangelol D (8)304153NTNTNT
Deoxypodophyllotoxin (9)0.0550.0820.210.0060.003NT
(-)-Deoxypodorhizone (10)1.853.24NTNTNT
Nemerosin (11)1.811.8NTNTNT
Anthriscinol methyl ether (12)131111NTNTNT
Elemicin (13)229.613NTNTNT
Anthriscusin (14)6.25.27.5NTNTNT
Morelensin (15)0.240.140.23NTNTNT
(-)-Hinokinin (16)4.87.37.6NTNTNT
Acteoside (17)355011NTNTNT
Isoacteoside (18)403210NTNTNT
Arenarioside (19)343416NTNTNT
Leucosceptoside A (20)423328NTNTNT
Ligupurpuroside A (21)26696.5NTNTNT
Ligupurpuroside C (22)494911NTNTNT
Ligupurpuroside B (23)>135>135120NTNTNT
Epicatechin (24)45NTNTNTNTNT
Epigallocatechin (25)14NTNTNTNTNT
Epigallocatechin gallate (26)9NTNTNTNTNT
Gallocatechin (27)14NTNTNTNTNT
Epicatechin gallate (28)14NTNTNTNTNT
Gallocatechin gallate (29)10NTNTNTNTNT
7-O-Galloylcatechin (30)41389NTNTNT
Gallic acid (31)19227.1NTNTNT
Gallic acid methylester (32)654318NTNTNT
Trigalloylgallic acid (33)109.32.9NTNTNT
1-O-Galloylglucose (34)604515NTNTNT
1,6-Di-O-galloylglucose (35)39298.1NTNTNT
Corilagin (36)13304.7NTNTNT
Prodelphidin B1 (37)13153.3NTNTNT
Prodelphidin B2 (38)15153.3NTNTNT
Apigenin (39)221526NTNTNT
Hispidulin (40)831767NTNTNT
Eupafolin (41)29616NTNTNT
Compound 42 555518NTNTNT
Compound 43 737329NTNTNT
Compound 44 334439NTNTNT
Cirsiliol (45)18219NTNTNT
Eupatorin (46)581544NTNTNT
Cirsilineol (47)1720373NTNTNT
Compound 48 221414NTNTNT
Compound 49 >267>267241NTNTNT
Chrysin (50)63851NTNTNT
Luteolin(51)311021NTNTNT
Baicalein (52)263011NTNTNT
6-Hydroxyluteolin (53)263013NTNTNT
Pectolinarigenin (54)1151064NTNTNT
Desmethoxylcentaureidin (55)24964NTNTNT
Jaceosidin (56)273327NTNTNT
Eupatilin (57)553558NTNTNT
7-Methoxyflavone (58)11987119NTNTNT
6-Methoxyflavone (59)3988398NTNTNT
1,3,11(13)-Elematrien-8β, 12-olide (60)6.9134.3NTNTNT
5α-Epoxyalantolactone (61)6.96.53.6NTNTNT
4β,5α-epoxy-1(10),11(13)-germacradiene-8,12-olide (62)123314NTNTNT
Alantolactone (63)6.96.94.7NTNTNT
Isoalantolactone (64)444129NTNTNT
11α,13-Dihydroalantolactone (65)>427>427>427NTNTNT
11α,13-Dihydroisoalantolactone (66)>427>42744NTNTNT
Rotundifolioside I (67)203718NTNTNT
Rotundifolioside J (68)162111NTNTNT
Rotundifolioside A (69)487131NTNTNT
Rotundifolioside H (70)183118NTNTNT
Rotundifolioside G (71)84>10846NTNTNT
Rotundifolioside E (72)>110>110>110NTNTNT
Rotundifolioside F (73)>108>108>108NTNTNT
Rotundioside F (74)17196.6NTNTNT
Rotundioside G (75)7.81517NTNTNT
Rotundioside T (76)13127.7NTNTNT
Rotundioside Q (77)343712NTNTNT
Rotundioside S (78)19348.9NTNTNT
Ursolic acid lactone (79)9088194NTNTNT
Ursolic acid (80)196514NTNTNT
Pomolic acid (81)555929NTNTNT
Corosolic acid (82)596944NTNTNT
2α,3α-Dihydoxy-urs-12-en-28-oic acid (83)553836NTNTNT
3-Epimaslinic acid (84)212119NTNTNT
Psoralen (85)40340376345177NT
Bergapten (86)16737167189214NT
Xanthotoxol (87)>43116289NTNTNT
8-Hydroxybergapten (88)1398.9104NTNTNT
Xanthotoxin (89)139741817348NT
Isopimpinellin (90)1515315985231NT
1,3-Dihydroxy-4-(2’-hydroxy-3’-hydroxymethyl-3’,4’-epoxybutyl)-N-methylacridone (91)0.0560.0561.76NTNTNT
1,3-Dihydroxy-4-[(Z)-3’-hydroxy-3’-methylbuten-1’-yl]-N-methylacridone (92)3086813NTNTNT
4β-Hydroxywithanolide E (93)NTNTNT0.20.21.6
withanolide S (94)NTNTNT19681NT
5α-O-Methylwithanolide S (95)NTNTNT213.6NT
5α-O-Butylwithanolide S (96)NTNTNT2.40.8NT
2-Hydro-3β-methoxy-4β-hydroxywithanolide E (97)NTNTNT1.91.7NT
Sitoindoside IX (98)NTNTNT0.836.1NT
Withaferine A (99)NTNTNT0.161.3NT
2,3-Dihydrowithaferine A (100)NTNTNT0.0220.51NT
24,25-Dihydrowithanolide D (101)NTNTNT0.0080.008860
Physapruin A (102)NTNTNT0.050.28NT
Withanolide F (103)NTNTNT1.41.6NT
Nivaphysalin A (104)NTNTNT>100>100NT
Nivaphysalin B (105)NTNTNT>100>100NT
Nivaphysalin C (106)NTNTNT5958NT
Liriodenine (107)NTNTNT3.13.6NT
Lysicamne (108)NTNTNT3216NT
Lanuginosine (109)NTNTNT1.34.5NT
14β-Hydroxytylophorine N-oxide (110)NTNTNT0.070.027NT
Tylophorinine N -oxide (111)NTNTNT0.0290.0048NT
3-Demethyl- 14α-hydroxyisotylocrebrine N -oxide (112)NTNTNT0.00830.00710.04
Tylophorine N -oxide (113)NTNTNT1.61.5NT
Isotylocrebrine N -oxide (114)NTNTNT0.380.25NT
3-Demethyl-14β-hydroxyisotylocrebrine (115)NTNTNT0.00280.0026NT
Tylophorine (116)NTNTNT0.0760.051NT
Isotylocrebrine (117)NTNTNT0.0480.025NT
7-Demethyltylophorine (118)NTNTNT0.0190.029NT
5-FU21131.1NTNTNT
DOXNTNTNT0.0150.013NT

Dox doxorubicin, 5-FU 5-fluorouracil (positive controls), NT not tested

Structures of polyacetylenes identified from a screen of plant extracts Anti-proliferative activities of compounds 1–118 (EC50, μM) against MK-1, HeLa, B16F10, MT-1, MT-2, and control PBMNC cells Dox doxorubicin, 5-FU 5-fluorouracil (positive controls), NT not tested

Lignans (Fig. 2)

After activity-guided fractionation against MK-1, HeLa, and B16F10 cells, seven lignans including deoxypodophyllotoxin (9), (-)-deoxypodorhizone (10), and related compounds were isolated from the roots of Anthriscus sylvestris (Apiaceae) [9]. From the fruits of the same plant, two other lignans (14 and 15) were isolated together with 9 and 10 after activity-guided fractionation against MK-1, HeLa, and B16F10 cells [10]. Deoxypodophyllotoxin (9) showed higher activity than polyacetylenes against these cell lines. Etoposide, a clinically used chemotherapeutic agent against small-cell lung cancer, malignant lymphoma, and acute leukemia is a derivative of a podophyllotoxin isolated from Podophyllum peltatum (Berberidaceae) [11]. Of note is that the EC50 value of deoxypodophyllotoxin (9) was in the nanomolar range across all cell lines tested including MT-1 and MT-2 cells (Table 3). Topoisomerase II-inhibited DNA breakage was recognized as the mechanism of action of Etoposide. The structural features that are crucial for the anti-topoisomerase II activity of podophyllotoxin derivatives have been roughly identified as: bulky 7β-bulky substituent, trans-lactone in ring D, dioxolane ring in ring A, quasi-axial configuration of ring E, and 4′-hydroxy group [12]. Structures of lignans identified from a screen of plant extracts

Phenylethanoids (Fig. 3)

After activity-guided fractionation against B16F10 cells, two active phenylethanoids, acteoside (17) and isoacteoside (18), were isolated from the leaves of Clerodendrum bungei and the bark of C. trichotomum (Laminaceae) [13]. Four other phenylethanoids including arenarioside (19) and leucosceptoside A (20) were isolated from the aerial parts of Lippia dulcis and L. canescens (Verbenaceae) together with some miscellaneous compounds after activity-guided fractionation against MK-1, HeLa, and B16F10 cells [14]. Furthermore, three other phenylethanoids (21–23) isolated from the leaves of Ligustrum purpurascens (Oleaceae) were also evaluated [15]. It was remarkable that the effect of phenylethanoids (17–23) against B16F10 cells was more potent than their effects against HeLa and MK-1 cells. Because the effects of compound 23 were extremely weak, this suggested the 3,4-dihydroxyphenethyl group is essential for the observed strong anti-proliferative activity. Furthermore, 3,4-dihydroxyphenethyl alcohol itself showed potent activity [13]. It is also known that treatment of phenylethanoids resulted in apoptotic cell death [16]. Structures of phenylethanoides identified from a screen of plant extracts

Polyphenols (Fig. 4)

Epidemiological studies have suggested that the consumption of green tea [Camellia sinensis (Theaceae)] provides protection against stomach cancer. In a rural area of northern Kyushu, Japan, a decreased risk of stomach cancer was also noted among people reporting a high consumption of green tea [17]. Fractionation of green tea extract, guided by the anti-proliferative activity against MK-1 cells, resulted in the isolation of six flavan-3-ols (24–29) together with the inactive glycosides of kaempferol and quercetin [18]. A study of their structure–activity relationships suggested that the presence of the three adjacent hydroxyl groups (pyrogallol or galloyl group) in the molecule is a key factor for enhancing the compound’s activity. Six active polyphenols (30–35) were isolated from the seeds of Rhynchosia volubilis (Fabaceae) after activity-guided fractionation against MK-1, HeLa, and B16F10 cells [19]. These compounds all showed much stronger inhibition against B16F10 cell growth than against HeLa and MK-1 cell growth. Gallic acid (31) with a free carboxyl group showed higher activity than its methyl ester (32). A hydrolysable tannin (36) and two condensed tannins (37, 38) isolated from Phyllanthus emblica (Phyllanthaceae) also showed potent activity [20] against three cell lines. It was proposed that the anti-cancer properties of polyphenols may be related to their ability to participate in a copper-dependent prooxidant mechanism [21]. Structures of polyphenols identified from a screen of plant extracts

Flavones (Fig. 5)

After activity-guided fractionation against MK-1, HeLa, and B16F10 cells, 11 active flavones (39–49) were isolated from the leaves of Lantana montevidensis (Verbenaceae) [22]. Concurrently, several related flavones (50–57) isolated from other plant materials and two synthetic ones (58, 59) were also evaluated. 5,7-Dihydroxy flavones (39, 50, 51), 5,7-dihydroxy-6-methoxy flavones (40, 41, 54, 55), and 6-methoxy flavone (59) were much stronger inhibitors of HeLa cell growth than B16F10 and MK-1 cell growth. In particular, compound 59 was a potent inhibitor of HeLa cell growth. Therefore, the 6-methoxy group is likely important for enhancing the anti-proliferative activity of flavones against HeLa cells. A synthetic flavone derivative, flavopiridol (Alvocidib), is being evaluated in clinical trials of ovarian and primary peritoneal cancers [23]. Structures of flavones identified from a screen of plant extracts as well as those derived synthetically

Sesquiterpenes (Fig. 6)

After activity-guided fractionation against MK-1, HeLa, and B16F10 cells, five active sesquiterpenes (60–64) were isolated from the roots of Inula helenium (Asteraceae) together with an inactive sesquiterpene (65) and a weak one (66) [24]. A structure–activity study suggested that the presence of an α-methylene-γ-lactone group is a key component required for the anti-proliferative activity. The thiol reactivity of the α-methylene-γ-lactone group may be responsible for the observed anti-proliferative activity [25]. Two norsesquiterpene glycosides from the roots of Phyllanthus emblica (Phyllanthaceae) exhibited potent activity (data not shown) although their aglycone and monoglucoside showed no inhibitory activity [20]. Structures of sesquiterpenes identified from a screen of plant extracts

Triterpene glycosides (Fig. 7) and triterpenes (Fig. 8)

From the bioactive fraction of the fruits of Bupleurum rotundifolium (Apiaceae), ten ursane-type triterpene glycosides were isolated and their anti-proliferative activities against MK-1, HeLa, and B16F10 cells were estimated [26]. All active glycosides (67–71) have a 13β, 28-epoxy ring system in the molecule except for 72 and 73, which have a 21β-hydroxy group. The glycosides of the other aglycones are almost inactive. Among the active glycosides, 69 and 71, which have a glucosyl group directly linked to the aglycone instead of a fucosyl group, were less potent. It is possible that the fucosyl group plays some role in the anti-proliferative activity. From the same fraction, 19 oleanane-type triterpene glycosides were also isolated and their anti-proliferative activities were evaluated [27]. Similar to the ursane-type triterpene glycosides, all active glycosides (74–78) have a 13β, 28-epoxy ring system in the molecule. In contrast to the ursane-type triterpene glycosides, compounds 77 and 78, which have a 21α-hydroxy group, had potent anti-proliferative activities. The configuration at the C-21 hydroxy group might influence the anti-proliferative activity. Structures of triterpene glycosides identified from a screen of plant extracts Structures of triterpenes identified from a screen of plant extracts After activity-guided fractionation against MK-1, HeLa and B16F10 cells, ten triterpenes were isolated from the aerial parts of Centella asiatica (Apiaceae) [28]. Some (79–84) of these triterpenes showed potent anti-proliferative activities. Similar to the results of the polyphenols, ursolic acid (80) with a free carboxyl group showed higher activity than its lactone (79). Ursolic acid (80) was previously reported to induce apoptoic cell death [29].

Coumarins and acridone alkaloids (Fig. 9)

After activity-guided fractionation against MK-1, HeLa, and B16F10 cells, 16 compounds were isolated from the aerial parts and roots of Boenninghausenia japonica (Rutaceae) [30]. Among them, an acridone alkaloid (91) showed very strong anti-proliferative activity against these three cell lines. The EC50 value of 91 was in the nanomolar range except for against B16F10 cells. Therefore, a 3′, 4′-epoxy group might be important for enhancing the anti-proliferative activity of acridone alkaloids. Furthermore, some furanocoumarins (85–90) showed potent anti-proliferative activities against HeLa cells. The furanocoumarins (87, 88) having an 8-hydroxy group showed more potent activity than those without the substituent (85, 86) and those with an 8-methoxy group (89, 90) against HeLa cells. Therefore, an 8-hydroxy group may be important for enhancing the anti-proliferative activity of these compounds against HeLa cells. Some furanocoumarins (85, 86, 89, 90) also showed moderate anti-proliferative activity against MT-1 and MT-2 cells (Table 3). A recent review reports that natural and synthetic coumarins have anticancer activity toward various cell lines [31]. Structures of coumarins and acridone alkaloids identified from a screen of plant extracts

Withanolides (Fig. 10)

After activity-guided fractionation against MT-1 and MT-2 cells, five active withanolides (93–97) were isolated from the aerial parts of Physalis pruinosa (Solanaceae) [32]. Structure–activity relationships suggested that the presence of a 5β, 6β epoxy group in the B-ring and a 4β-hydroxy group in the A-ring were important for the observed activities. The aliphatic ether side chain at C-5 also seems to increase the activity because as the side chain is lengthened, the activity increases. Because the EC50 value for 4β-hydroxywithanolide E (93) was in the nanomolar range against both MT-1 and MT-2 cells, 31 other withanolides were also evaluated [33]. Except for compound 98, none of the glycosides showed any activity against the ATL cell lines. Because compound 98 has a 5β, 6β-epoxy group as well as a 4β-hydroxy group, we predicted it might show potent activity. However, the activity of the corresponding deglycosylated compound (99) was approximately four times greater than that of its glucoside (98). These results indicated that the presence of a sugar moiety should reduce the anti-proliferative effects. The importance of the 5β, 6β-epoxy group, and 4β-hydroxy group was further supported by the analysis of compound 100 because it showed the second strongest anti-proliferative activity. The activities of 99, having a double bond between C-2 and C-3, were weaker than those for 100, suggesting the double bond between C-2 and C-3 might reduce the activity. Because compound 102 showed greater activity when compared with compound 103, the importance of a 4β-hydroxy group was further supported. Compared with the compounds having the 5β, 6β-epoxy group, the activities of the compounds (104–106) having other types of epoxy groups (6α, 7α-epoxy group in the B-ring and/or 24α, 25α-epoxy group in the E-ring) were significantly lower. The position of the epoxy group and/or the configuration of the epoxy group seem to be important for the activity. Compound 106 containing a 15β-hydroxy group showed moderate activity while compound 105 containing a 15α-hydroxy group did not show any activity. This indicated that the configuration of the hydroxy group at C-15 may influence a compound’s activity. Finally, the EC50 value of 24, 25-dihydrowithanolide D (101), the most potent withanolide-type inhibitor, was 8 nM against both cells. In contrast, the cytotoxic effect (860 nM) of 101 toward normal cells was observed at a concentration about 100 times higher than those observed for the ATL cell lines. Furthermore, compound 101 was confirmed to induce dose-dependent apoptosis against MT-1, MT-2, and fresh ATL cells [33]. Therefore, 24, 25-dihydrowithanolide D (101) may be a promising chemotherapeutic candidate. Structures of withanolides identified from a screen of plant extracts Recently inhibition of the growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest by 4β-hydroxywithanolide E (93) have been reported [34]. Further, induction of apoptosis in leukemia cells by targeting the activation of a neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase by withanolide D have been also reported [35]. Wang et al. suggested that Hsp90 inhibition by the withanolides is correlated with their ability to induce cancer cell death [36].

Aporphine and phenanthroindolizidine alkaloids (Fig. 11)

After activity-guided fractionation against MT-1 and MT-2 cells, three active aporphine alkaloids (107–109) were isolated from the leaves of Annona reticulata and A. squamosa (Annonaceae) [37]. Liriodenine (107) showed accumulation of Sub-G1 stage cells in the MT-1 and MT-2 cell population, suggesting induction of apoptosis. A structure–activity relationship analysis suggested that the presence of a 1, 2-methylenedioxy group seemed to enhance activity. A similar conclusion on the structure–activity relationship was also obtained by Liu et al. [38]. Structures of aporphine and phenanthroindolizidine alkaloids identified from a screen of plant extracts Six phenanthroindolizidine alkaloids (110–115) were isolated from the aerial parts of Tylophora tanakae (Asclepiadaceae) by activity-guided fractionation [39]. In addition to 110–115, three phenanthroindolizidine alkaloids (116–118) obtained from other plants were examined for their anti-proliferative activity against MT-1 and MT-2 cells. The EC50 values of all alkaloids except for compound 113 were in the low nanomolar range. The results suggested that the presence of a 2-methoxy functionality, the methyl group of a 7-methoxy functionality, and an N-oxide moiety appear to reduce the potency of the anti-proliferative activity [39]. Phenanthroindolizidine alkaloids are cytotoxic to multidrug-resistant cells [40], inhibiting the enzyme dihydrofolate reductase [41]. The in vivo efficacy of a new phenanthroindolizidine alkaloid derivative (YPC-10157) was recently evaluated [42].

Conclusions

Cytotoxicity against selected cancer cell lines was characterized and could be explained by identifying the active principles responsible for the observed effects. The polyacetylenes was more potent against MK-1 cells than against HeLa and B16F10 cells. The EC50 value of the most potent polyacetylene (2) against MK-1 cells was 1.2 μM (Fig. 12). The compounds (17–22) having a 3, 4-dihydroxyphenethyl group also showed remarkable anti-proliferative effects against B16F10 cells (Fig. 12). Interestingly, some 6-methoxyflavone derivatives (40, 41, 54, 55, 59) and 8-hydroxy furanocoumarins (87, 88) showed strong inhibition against HeLa cell growth (Fig. 12).
Fig. 12

Differences in the specific selectivity of selected compounds against various cancer cell lines

Differences in the specific selectivity of selected compounds against various cancer cell lines The compounds whose EC50 values were less than one nanomolar (<1 nM) were not selective for specific cell types. This group included two lignans (9, 15), one acridone alkaloid (91), six withanolides (93, 98–102), and eight phenanthroindolizidine alkaloids (110–112, 114–118). Because the cytotoxic effect of 24, 25-dihydrowithanolide D (101) toward normal cells was observed at a concentration about 100 times higher than against the ATL cell lines, withanolide was concluded to be the most promising chemotherapeutic candidate from our experiments.
  37 in total

1.  A phase 2 trial of flavopiridol (Alvocidib) and cisplatin in platin-resistant ovarian and primary peritoneal carcinoma: MC0261.

Authors:  Keith C Bible; Prema P Peethambaram; Ann L Oberg; William Maples; David L Groteluschen; Matthew Boente; Jill K Burton; Leigh C Gomez Dahl; Jennifer D Tibodeau; Crescent R Isham; Jacie L Maguire; Viji Shridhar; Andrea K Kukla; Kalli J Voll; Mathew J Mauer; Alexander D Colevas; John Wright; L Austin Doyle; Charles Erlichman
Journal:  Gynecol Oncol       Date:  2012-06-01       Impact factor: 5.482

2.  Antiproliferative constituents in plants 14. Coumarins and acridone alkaloids from Boenninghausenia japonica NAKAI.

Authors:  Norihito Chaya; Kazuko Terauchi; Yuriko Yamagata; Junei Kinjo; Hikaru Okabe
Journal:  Biol Pharm Bull       Date:  2004-08       Impact factor: 2.233

3.  Antiproliferative constituents in umbelliferae plants. IV. Constituents in the fruits of Anthriscus sylvestris Hoffm.

Authors:  R Ikeda; T Nagao; H Okabe; Y Nakano; H Matsunaga; M Katano; M Mori
Journal:  Chem Pharm Bull (Tokyo)       Date:  1998-05       Impact factor: 1.645

Review 4.  Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach.

Authors:  Kuo-Hsiung Lee
Journal:  J Nat Prod       Date:  2010-03-26       Impact factor: 4.050

5.  Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (IV): phenanthroindolizidine alkaloids from Tylophora tanakae leaves.

Authors:  Daisuke Nakano; Kenji Ishitsuka; Mizuki Ikeda; Ryota Tsuchihashi; Masafumi Okawa; Hikaru Okabe; Kazuo Tamura; Junei Kinjo
Journal:  J Nat Med       Date:  2015-04-04       Impact factor: 2.343

6.  Activity-guided fractionation of green tea extract with antiproliferative activity against human stomach cancer cells.

Authors:  Junei Kinjo; Tsuneatsu Nagao; Takashi Tanaka; Gen-ichiro Nonaka; Masafumi Okawa; Toshihiro Nohara; Hikaru Okabe
Journal:  Biol Pharm Bull       Date:  2002-09       Impact factor: 2.233

7.  Antiproliferative constituents in umbelliferae plants. III. Constituents in the root and the ground part of Anthriscus sylvestris Hoffm.

Authors:  R Ikeda; T Nagao; H Okabe; Y Nakano; H Matsunaga; M Katano; M Mori
Journal:  Chem Pharm Bull (Tokyo)       Date:  1998-05       Impact factor: 1.645

8.  4beta-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest.

Authors:  Ching-Yu Yen; Chien-Chih Chiu; Fang-Rong Chang; Jeff Yi-Fu Chen; Chi-Ching Hwang; You-Cheng Hseu; Hsin-Ling Yang; Alan Yueh-Luen Lee; Ming-Tz Tsai; Zong-Lun Guo; Yu-Shan Cheng; Yin-Chang Liu; Yu-Hsuan Lan; Yu-Ching Chang; Ying-Chin Ko; Hsueh-Wei Chang; Yang-Chang Wu
Journal:  BMC Cancer       Date:  2010-02-18       Impact factor: 4.430

9.  Antiproliferative constituents in plants 9. Aerial parts of Lippia dulcis and Lippia canescens.

Authors:  Fumiko Abe; Tsuneatsu Nagao; Hikaru Okabe
Journal:  Biol Pharm Bull       Date:  2002-07       Impact factor: 2.233

10.  Withanolides-induced breast cancer cell death is correlated with their ability to inhibit heat protein 90.

Authors:  Hui-Chun Wang; Yi-Ling Tsai; Yang-Chang Wu; Fang-Rong Chang; Mei-Hsin Liu; Wen-Ying Chen; Chin-Chung Wu
Journal:  PLoS One       Date:  2012-05-31       Impact factor: 3.240
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  5 in total

Review 1.  Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review).

Authors:  Abbas Salihi; Mohammed A Al-Naqshabandi; Zhikal Omar Khudhur; Zjwan Housein; Harmand A Hama; Ramyar M Abdullah; Bashdar Mahmud Hussen; Twana Alkasalias
Journal:  Mol Med Rep       Date:  2022-05-26       Impact factor: 3.423

2.  Imperatorin as a Promising Chemotherapeutic Agent Against Human Larynx Cancer and Rhabdomyosarcoma Cells.

Authors:  Aneta Grabarska; Krystyna Skalicka-Woźniak; Michał Kiełbus; Magdalena Dmoszyńska-Graniczka; Paulina Miziak; Justyna Szumiło; Ewa Nowosadzka; Krystyna Kowalczuk; Sherief Khalifa; Jolanta Smok-Kalwat; Janusz Klatka; Krzysztof Kupisz; Krzysztof Polberg; Adolfo Rivero-Müller; Andrzej Stepulak
Journal:  Molecules       Date:  2020-04-28       Impact factor: 4.411

3.  6-Methoxyflavone induces S-phase arrest through the CCNA2/CDK2/p21CIP1 signaling pathway in HeLa cells.

Authors:  Chaihong Zhang; Yuchong Quan; Lijuan Yang; Yingying Bai; Yongxiu Yang
Journal:  Bioengineered       Date:  2022-03       Impact factor: 3.269

Review 4.  Recent Advances in the Antiproliferative and Proapoptotic Activity of Various Plant Extracts and Constituents against Murine Malignant Melanoma.

Authors:  Daria-Antonia Dumitraș; Sanda Andrei
Journal:  Molecules       Date:  2022-04-17       Impact factor: 4.927

5.  Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma (VII): Active Principles from Thuja occidentalis L.

Authors:  Daisuke Nakano; Kenji Ishitsuka; Madoka Ishihara; Ryota Tsuchihashi; Masafumi Okawa; Kazuo Tamura; Junei Kinjo
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  5 in total

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