In Vitro Growth Inhibitory Effects of Cytochalasins and Derivatives in Cancer Cells

Abstract

The in vitro anticancer activity of eight natural cytochalasins and three hemisynthetic derivatives of cytochalasin B on six cancer cell lines was evaluated. The IC₅₀ in vitro growth inhibitory concentrations, as determined by an MTT colorimetric assay, ranged between 3 and 90 µM and did not relate to the intrinsic sensitivity of the cancer cell lines to proapoptotic stimuli. Structure activity relationship (SAR) analyses revealed that the presence of an unmodified hydroxyl group at C-7 of the perhydroisoinsolyl-1-one residue as well as the functionalities and the conformational freedom of the macrocycle are all important features for cytochalasin-mediated anticancer activities in vitro. Computer-assisted phase-contrast microscopy revealed two groups of cytochalasins, i.e., cytotoxic versus cytostatic ones. Our data open new possibilities for tuning cytochalasin targets and developing nontoxic, cytostatic cytochalasins to combat cancers associated with poor prognoses, such as those that display intrinsic resistance to proapoptotic stimuli.

cytochalasins - cancer - in vitro - cytotoxic - cytostatic - quantitative videomicroscopy

References

• 1 Carter S B. Effects of cytochalasins on mammalian cells.  Nature. 1967;  213 261-264
• 2 Aldridge D C, Armstrong J J, Speake R N, Turner W B. The cytochalasins, a new class of biologically active mould metabolites.  J Chem Soc Chem Commun. 1967;  3 26-27
• 3 Vurro M, Bottalico A, Capasso R, Evidente A. Cytochalasins from phytopatogenic Ascochyta and Phoma species. Upadahyay RK, Mukerji KG Toxins in Plants Disease Development and Evolving Biotechnology. New Delhi; Oxford & IBH Publishing Co. 1997: 127-147
• 4 Capasso R, Evidente A, Ritieni A, Randazo G, Vurro M, Bottalico A. Ascochalasin, a new cytochalasin from Ascochyta heteromorpha.  J Nat Prod. 1988;  51 567-571
• 5 Capasso R, Evidente A, Randazo G, Ritieni A, Vurro M, Bottalico A, Logrieco A. Isolation of cytochalasins A and B from Ascochyta heteromorpha.  J Nat Prod. 1987;  50 989-990
• 6 Evidente A, Lanzetta R, Capasso R, Vurro M, Bottalico A. Cytochalasins U and V, two new cytochalasans, from Phoma exigua var. heteromorpha.  Tetrahedron. 1992;  48 6317-6324
• 7 Evidente A, Capasso R, Vurro M, Bottalico A. Cytochalasin W, a new 24-oxa[14]cytochalasan from Phoma exigua var. heteromorpha.  Nat Toxins. 1996;  4 53-57
• 8 Capasso R, Evidente A, Vurro M. Cytochalasins from Phoma exigua var. heteromorpha.  Phytochemistry. 1991;  30 3945-3950
• 9 Evidente A, Andolfi A, Vurro M, Zonno M C, Motta A. Cytochalasins Z1, Z2, and Z3, three 24-oxa[14]cytochalasans produced by Pyrenophora semeniperda.  Phytochemistry. 2002;  60 45-53
• 10 Evidente A, Andolfi A, Vurro M, Zonno M C, Motta A. Cytochalasins Z4, Z5, and Z6, three new 24-Oxa[14]cytochalasans produced by Phoma exigua var. heteromorpha.  J Nat Prod. 2003;  66 1540-1544
• 11 Thilly W G, Liber H L, Wogan G N. Toxicity and structure-activity relationships of cytochalasins. Tanenbaum SW Cytochalasins and Cell Biological Aspects. Amsterdam; Elsevier North-Holland Biomedical Press 1978: 53-64
• 12 Yahara I, Harada F, Sekita S, Yoshihira K, Natori S. Correlation between effects of 24 different cytochalasins on cellular structures and cellular events and those on actin in vitro.  J Cell Biol. 1982;  92 69-78
• 13 Choi B H, Park J A, Kim K R, Lee G I, Lee Y T, Choe H, Ko S H, Kim M H, Seo Y H, Kwak Y G. Direct block of cloned hKv1.5 channel by cytochalasins, actin-disrupting agents.  Am J Physiol Cell Physiol. 2005;  289 C425-C436
• 14 Goddette D W, Frieden C. Actin polymerization. The mechanism of action of cytochalasin D.  J Biol Chem. 1986;  261 15974-15980
• 15 Udagawa T, Yuan J, Panigrahy D, Chang Y H, Shah J, D'Amato R J. Cytochalasin E, an epoxide containing Aspergillus-derived fungal metabolite, inhibits angiogenesis and tumor growth.  J Pharmacol Exp Ther. 2000;  294 421-427
• 16 Mel'nik V. A Key to the fungi of the genus Ascochyta Lib. (Coelomycetes). Mel'nik VA, Braun U, Hagedorn G Mitteilungen von der Biologischen Bundesanstalt für Land- und Forstwirtschaft Berlin-Dahlem, Heft 379. Berlin; Parey Buchverlag 2000: 1-192
• 17 Cimmino A, Andolfi A, Berestetskiy A, Evidente A. Production of phytotoxins by Phoma exigua var. exigua, a potential mycoherbicide against perennial thistles.  J Agric Food Chem. 2008;  56 6304-6309
• 18 Bottalico A, Capasso R, Evidente A, Randazzo G, Vurro M. Cytochalasins: structure activity relationships.  Phytochemistry. 1990;  29 93-96
• 19 Bruyère C, Lonez C, Duray A, Cludts S, Ruysschaert J M, Saussez S, Yeaton P, Kiss R, Mijatovic T. Considering temozolomide as a novel potential treatment for oesophageal cancer.  Cancer. , , in press
  
• 20 Ingrassia L, Lefranc F, Dewelle J, Pottier L, Mathieu V, Spiegl-Kreinecker S, Sauvage S, El Yazidi M, Dehoux M, Berger W, Van Quaquebeke E, Kiss R. Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents.  J Med Chem. 2009;  52 1100-1114
• 21 Mathieu V, Pirker C, Martin de Lassalle E, Vernier M, Mijatovic T, De Neve N, Gaussin J-F, Dehoux M, Lefranc F, Berger W, Kiss R. The sodium pump alpha1 sub-unit: a disease progression-related target for metastatic melanoma treatment.  J Cell Mol Med. 2009;  13 3960-3972
• 22 Mijatovic T, Mathieu V, Gaussin J-F, De Nève N, Ribaucour F, Van Quaquebeke E, Dumont P, Darro F, Kiss R. Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers.  Neoplasia. 2006;  8 402-412
• 23 Mathieu V, Le Mercier M, De Neve N, Sauvage S, Gras T, Roland I, Lefranc F, Kiss R. Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model.  J Invest Dermatol. 2007;  127 2399-2410
• 24 Hayot C, Debeir O, Van Ham P, Van Damme M, Kiss R, Decaestecker C. Characterization of the activities of actin-affecting drugs on tumor cell migration.  Toxicol Appl Pharmacol. 2006;  211 30-40
• 25 Stehn J R, Schevzov G, O'Neill G M, Gunning P W. Specialisation of the tropomyosin composition of actin filaments provides new potential targets for chemotherapy.  Curr Cancer Drug Targets. 2006;  6 245-256
• 26 Decaestecker C, Debeir O, Van Ham P, Kiss R. Can anti-migratory drugs be screened in vitro? A review of 2D and 3D assays for the quantitative analysis of cell migration.  Med Res Rev. 2007;  27 149-176
• 27 Arcangeli A, Crociani O, Lastraioli E, Masi A, Pillozzi S, Becchetti A. Targeting ion channels in cancer: a novel frontier in antineoplastic therapy.  Curr Med Chem. 2009;  16 66-93
• 28 Shen Z, Yang Q, You Q. Researches toward potassium channels on tumor progressions.  Curr Top Med Chem. 2009;  9 322-329
• 29 Wulff H, Castle N A, Pardo L A. Voltage-gated potassium channels as therapeutic targets.  Nat Rev Drug Discov. 2009;  8 982-1001
• 30 Prevarskaya N, Skryma R, Shuba Y. Ion channels and the hallmarks of cancer.  Trends Mol Med. 2010;  16 107-121
• 31 Negulyaev Y A, Khaitlina S Y, Hinssen H, Shumilina E V, Vedernikova E A. Sodium channel activity in leukemia cells is directly controlled by actin polymerization.  J Biol Chem. 2000;  275 40933-40937
• 32 Wang Z, Eldstrom J R, Jantzi J, Moore E D, Fedida D. Increased focal Kv4.2 channel expression at the plasma membrane is the result of actin depolymerization.  Am J Physiol Heart Circ Physiol. 2004;  286 H749-H759
• 33 Staruschenko A, Negulyaev Y A, Moracheskaya E A. Actin cytoskeleton disassembly affects conductive properties of stretch-activated cation channels in leukaemia cells.  Biochim Biophys Acta. 2005;  1669 53-60
• 34 Bonnet S, Archer S L, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee C T, Lopaschuk G D, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter C J, Andrade M A, Thebaud B, Michelakis E D. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.  Cancer Cell. 2007;  11 37-51
• 35 Bielanska J, Hernandez-Losa J, Perez-Verdaguer M, Moline T, Somoza R, Ramon Y, Cajal S, Condom E, Ferreres J C, Felipe A. Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer.  Curr Cancer Drug Targets. 2009;  9 904-914