3-Hydrogenkwadaphnin from Dendrostellera lessertii Induces Differentiation and Apoptosis in HL-60 Cells

Abstract

3-Hydrogenkwadaphnin (3-HK) is a new diterpene ester, recently isolated from the leaves of Dendrostellera lessertii with potent anti-tumoral and anti-metastatic activities. Herein, we report that 3-HK induces differentiation and apoptosis in HL-60 cells. The drug at 2.5 - 40 nM inhibited proliferation of HL-60 cells after 24 - 96 h of treatment. Cell viability was also decreased by 57 % after 96 h treatment with the drug. NBT reducing assay and phagocytic activity revealed that the inhibition of proliferation is associated with differentiation especially toward macrophages-like morphology. Indeed, the drug at 2.5 - 10 nM induced differentiation by 5 - 49 % in HL-60 cells. Acridine orange/ethidium bromide (AO/EtBr) double staining and DNA fragmentation assays revealed that apoptosis occurred after differentiation of HL-60 cells. Guanosine at 50 μM decreased the apoptotic cell death and the differentiation caused by the drug. Therefore, GTP depletion, as a result of inhibition of inosine monophosphate dehydrogenase (IMPDH), is considered as one of the main reasons for differentiation and apoptotic cell death by this new drug.

Apoptosis - Dendrostellera lessertii - differentiation - HL-60 cells - leukemia

References

• 1 Sachs L. The control of hematopoiesis and leukemia: from basic biology to the clinic.  Proc Natl Acad Sci USA. 1996;  93 4742-9
• 2 Bruserud O, Gjertsen B T. New strategies for the treatment of acute myelogenous leukemia: differentiation induction - present use and future possibilities.  Stem Cells. 2000;  18 157-65
• 3 Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M, Takemura Y. et al . Acridones as inducers of HL-60 cell differentiation.  Leuk Res. 1999;  23 263-9
• 4 Koeffler H P, Bar-Eli M, Territo M C. Phorbol ester effect on differentiation of human myeloid leukemia cell lines blocked at different stages of maturation.  Cancer Res. 1981;  41 919-26
• 5 Collins S J, Ruscetti F W, Gallagher R E, Gallo R C. Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds.  Proc Natl Acad Sci USA. 1978;  75 2458-62
• 6 Martin S J, Bradley J G, Cotter T G. HL-60 cells induced to differentiate towards neutrophils subsequently die via apoptosis.  Clin Exp Immunol. 1990;  79 448-53
• 7 Kerr J F, Winterford C M, Harmon B V. Apoptosis: Its significance in cancer and cancer therapy.  Cancer. 1994;  73 2013-26
• 8 Shu Y Z. Recent natural products based drug development: a pharmaceutical industry perspective.  J Nat Prod. 1998;  61 1053-71
• 9 Hall I H, Kasai R, Wu R Y, Tagahara K, Lee K H. Antitumor agents LV: Effects of genkwadaphnin and yuanhuacine on nucleic acid synthesis of P-338 lymphocytic leukemia cells.  J Pharm Sci. 1982;  71 1263-7
• 10 Yazdanparast R, Sadeghi H. Nucleic acid synthesis in cancerous cells under the effect of gnidilatimonoein from Daphne mucronata .  Life Sci. 2004;  74 1869-76
• 11 Stanoeva E, He W, De Kimpe N. Natural and synthetic cage compounds incorporating the 2,9,10-trioxatricyclo[4.3.1.0^3,8]decane type moiety.  Bioorg Med Chem. 2005;  13 17-28
• 12 Jayaram H N, Cooney D A, Grusch M. Krupitza G. Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis.  Curr Med Chem. 1999;  6 561-74
• 13 Yazdanparast R, Mianabadi M, Abdolmohammadi M H. Anti-tumor activity of Dendrostellera lessertii and the inhibitory effect of one of its purified diterpene ester on wehi-164 cell adhesion.  Nat Prod Sci. 2003;  9 161-6
• 14 Sadeghi H, Yazdanparast R. Effects of Dendrostellera lessertii on the intracellular alkaline phosphatase activity of four human cancer cell lines.  J Ethnopharmacol. 2003;  86 11-4
• 15 Yazdanparast R, Mianabadi M. The effect of active compound of Dendrostellera lessertii on the adhesive property of human platelets and HL-60 cells.  Life Sci. 2004;  75 733-9
• 16 Vistica D T, Skehan P, Scudiero D, Monks A, Pittman A, Boyd M R. Tetrazolium-based assays for cellular viability: a critical examination of selected parameters affecting formazan production.  Cancer Res. 1991;  51 2515-20
• 17 Yamada T, Okajima F, Akbar M, Tomura H, Narita T, Yamada T. et al . Cell cycle arrest and the induction of apoptosis in pancreatic cancer cells exposed to adenosine triphosphate in vitro .  Oncol Rep. 2002;  9 113-7
• 18 Sakashita A, Nakamaki T, Tsuruoka N, Honma Y, Hozumi M. Granulocyte colony-stimulating factor, not granulocyte-macrophage colony-stimulating factor, co-operates with retinoic acid on the induction of functional N-formyl-methionyl-phenylalanine receptors in HL-60 cells.  Leukemia. 1991;  5 26-31
• 19 Goliaei B, Deizadji A. Effects of hyperthermia and granulocyte-macrophage colony-stimulating factor on the differentiation of human leukemic cell line U937.  Leuk Res. 1998;  22 705-10
• 20 Jing Y, Nakajo S, Xia L, Nakaya K, Fang Q, Waxman S, Han R. Boswellic acid acetate induces differentiation and apoptosis in leukemia cells.  Leuk Res. 1999;  23 43-50
• 21 Rovera G, Santoli D, Damsky C. Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester.  Proc Natl Acad Sci USA. 1979;  76 2779-83
• 22 Inai K, Tsutani H, Yumauchi T, Fukushima T, Iwasaki H, Imamura S. et al . Differentiation induction in non-lymphocytic leukemia cells upon treatment with mycophenolate mofetil.  Leuk Res. 2000;  24 761-8
• 23 Watson R W, Rotstein O D, Parodo J, Bitar R, Hackam D, Marshall J C. Granulocytic differentiation of HL-60 cells results in spontaneous apoptosis mediated by increased caspase expression.  FEBS Lett. 1997;  412 603-9