Cytotoxic and Anti-Inflammatory Activity of Labdane and cis-Clerodane Type Diterpenes

Abstract

Two labdane type diterpenes, labd-13(E)-ene,-8α,15-diol (1) and labd-13(E)-ene,-8α,15-yl acetate (2) were isolated from the hexane extract of Cistus creticus subsp. eriocephalus (Viv.) Greuter & Burdet leaves, while (+)-19-acetoxy-cis-clerodan-3-en-15-oic acid (3) was isolated from the hexane extract of Cistus monspeliensis L. leaves. The compounds were examined for their in vitro cytostatic and cytotoxic activity against nine human leukemic cell lines, three of which exhibited a multidrug resistant phenotype. They were also evaluated for their anti-inflammatory activity in vivo on the back of hairless mice. The cytostatic and cytotoxic activity of the tested diterpenes followed the order 1>2>3. Topical application of the diterpenes on barrier disrupted skin did not seem to have a significant contribution to the repair rate of the skin barrier.

Abbreviations

GI₅₀:growth inhibition 50

LC₅₀:lethal concentration 50

MED:minimum erythymal dose

MDR:multidrug resistant

MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

PBS:phosphate buffered saline

RI:retention indices

R_t:retention time

TEWL:transepidermal water loss

TGI:total growth inhibition

Key words

Cistus creticus subsp. eriocephalus, Cistus monspeliensis Cistaceae, labdane diterpenes, clerodane diterpenes, cytostatic/cytotoxic effect, anti-inflammatory activity

References

• 1 Gülz P G, Herrmann T, Hangst K. Leaf trichomes in the genus Cistus .  Flora. 1996;  191 85-104
• 2 Greuter W, Burdet H M, Long G. Conservatoire et Jardin Botaniques, Ville de Geneve.  Med-Checklist. 1984;  Vol. I 315-6
• 3 Anastasaki T, Demetzos C, Perdetzoglou D, Gazouli M, Loukis A, Harvala A. Analysis of labdane type-diterpenes from Cistus creticus (subsp. creticus and subsp. eriocephalus), by GC and GC-MS.  Planta Med.. 1999;  65 735-9
• 4 Polunin O. Flowers of Europe a field guide. Oxford University Press 1969: 254
• 5 Angelopoulou D, Demetzos C, Dimas K, Perdetzoglou D, Loukis A. Essential oils and hexane extracts of Cistus monspeliensis. Cytotoxic activity of ent-13-epi- manoyl oxide and its isomers.  Planta Med.. 2001;  67 168-71
• 6 Dimas K, Demetzos C, Marsellos M, Sotiriadou R, Malamas M, Kokinopoulos D. Cytotoxic activity of labdane type diterpenes against human leukemic cell lines in vitro .  Planta Med.. 1998;  64 208-11
• 7 De la Heras B, Hoult J R. Non-cytotoxic inhibition of macrophage eicosanoid biosynthesis and effects on leukocyte functions and reactive oxygen species of two novel anti-inflammatory plant diterpenoids.  Planta Med.. 1994;  60 501-6
• 8 Tabacit C, Bard M. Etude chimio-taxonomique dans le gene Cistus .  Phytochemistry. 1971;  10 3039-109
• 9 Dimas K, Demetzos C, Angelopoulou D, Kolokouris A, Mavromoustakos T. Biological activity of myricetin and its derivatives against human leukemic cell lines in vitro .  Pharmacological Res.. 2000;  42 475-8
• 10 Monks A, Scudiero D, Skehan P, Shomaker R, Paull K, Vistica D, Hose C. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines.  JNCI. 1991;  83 757-66
• 11 Alley M C, Scudiero A D, Monks A, Hursey M L, Czerwinski M J, Fine D L, Abbott B J. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay.  Cancer Res.. 1987;  48 589-601
• 12 Haratake A, Ushida Y, Schmuth M, Tanno O, Yasuda R, Epstein J H, Elias P M, Holleran W M. UV-B induced alterations in permeability barrier function: roles for epidermal hyperproliferation and thymocyte-mediated response.  J Invest Dermatol. 1997;  108 769-75
• 13 Paull K D, Shomaker R H, Hodes L, Monks A, Scudiero D A, Rubinstein L, Plowman J, Boyd M R. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: Development of mean graph and COMPARE algorithm.  JNCI. 1989;  81 1088-92
• 14 De la Heras B, Villar a, Vivas J M, Hoult J R. Novel anti-inflammatory plant labdanes: comparison of in vitro properties with aspirin and indomethacin.  Agents Actions. 1994;  42 114-7
• 15 Tao X, Lipsky P E. The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. Rheum. Dis. Clin.  North Am.. 2000;  26 29-50
• 16 Alcaraz M J, Jimenez M J, Valverde S, Sanz J, Rabanal R M. Anti-inflammatory compounds from Sideritis javalambrensis n-hexane extract.  Journal of Natural Products. 1989;  52 1088-91