Skip to main content

Advertisement

SpringerLink
Log in

Furano-sesquiterpene from soft coral, Sinularia kavarittiensis: induces apoptosis via the mitochondrial-mediated caspase-dependent pathway in THP-1, leukemia cell line

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Bioassay directed fractionation and purification led to the successful isolation of a furano sesquiterpene, Methyl 5-[(1E,5E)-2,6-Dimethyl octa-1,5,7-trienyl] furan-3-carboxylate (MDTFC), a bioactive component from a soft coral, Sinularia kavarittiensis. Its structure was determined by analyzing 1H, 13C NMR and FAB-MS. The results show that MDTFC could efficiently and selectively inhibit the proliferation of several human cancer cell lines. Among all the cell lines, THP-1 was found to be most sensitive (IC50 29.59 μM), whereas the peripheral blood mononuclear cells were least effected (IC50 464.16 μM). The molecular mechanism of MDTFC mediated apoptosis was investigated for the first time. Induction of apoptosis in THP-1 cells was characterized by cell membrane blebbing, chromatin condensation, DNA fragmentation, and decrease in level of pro-caspases 3, 9 and increase in Bax/Bcl-2 ratio. Our results were further strengthened through cleavage of poly (ADP-ribose) polymerase, reduction of mitochondrial membrane potential (Ψm) and cytosolic release of cytochrome c, which are key events during apoptosis. Moreover, phosphatidyl serine exposure and appearance of sub-G1 peak also demonstrated cell death, when analyzed by flow cytometry. DNA fragmentation was prevented moderately when pretreated with caspase-9 inhibitor (Z-LEHD-FMK) and largely with caspase-3 inhibitor (Z-DEVD-FMK). In summary, MDTFC mediated apoptosis involves mitochondria-dependent pathway and the present compound of marine origin might have a therapeutic value against human cancer cell lines and especially on leukemia cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Donia M, Hamann MT (2003) Marine natural products and their potential applications as anti-infective agents. Lancet Infect Dis 3:338–348. doi:10.1016/S1473-3099(03)00655-8

    Article  CAS  PubMed  Google Scholar 

  2. Randazzo A, Bifulco G, Giannini C, Bucci M, Debitus C, Cirino G, Gomez-Paloma L (2001) Halipeptins A and B: two novel potent anti-inflammatory cyclic depsipeptides from the Vanuatu marine sponge Haliclona species. J Am Chem Soc 123:10870–10876. doi:10.1021/ja010015c

    Article  CAS  PubMed  Google Scholar 

  3. Simmons TL, Andrianasolo E, McPhail K, Flatt P, Gerwick WH (2005) Marine natural products as anticancer drugs. Mol Cancer Ther 4:333–342

    CAS  PubMed  Google Scholar 

  4. Jacobson MD, Weil M, Raff MC (1997) Programmed cell death in animal development. Cell 88:347–354. doi:10.1016/S0092-8674(00)81873-5

    Article  CAS  PubMed  Google Scholar 

  5. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462. doi:10.1126/science.7878464

    Article  CAS  PubMed  Google Scholar 

  6. Choi YH, Kong KR, Kim YA, Jung KO, Kil JH, Rhee SH, Park KY (2003) Induction of Bax and activation of caspases during beta-sitosterol-mediated apoptosis in human colon cancer cells. Int J Oncol 23:1657–1662

    CAS  PubMed  Google Scholar 

  7. Rosse T, Olivier R, Monney L, Rager M, Conus S, Fellay I, Jansen B, Borner C (1998) Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391:496–499. doi:10.1038/35160

    Article  CAS  PubMed  Google Scholar 

  8. Stennicke HR, Salvesen GS (1999) Catalytic properties of the caspases. Cell Death Differ 6:1054–1059. doi:10.1038/sj.cdd.4400599

    Article  CAS  PubMed  Google Scholar 

  9. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308. doi:10.1126/science.281.5381.1305

    Article  CAS  Google Scholar 

  10. Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339–352. doi:10.1016/S0092-8674(00)81477-4

    Article  CAS  PubMed  Google Scholar 

  11. Yu S, Deng Z, van Ofwegen L, Proksch P, Lin W (2006) 5, 8-Epidioxysterols and related derivatives from a Chinese soft coral Sinularia flexibilis. Steroids 71:955–959. doi:10.1016/j.steroids.2006.07.002

    Article  CAS  PubMed  Google Scholar 

  12. Bowden BF, Coll JC, de Silva ED, de Costa MSL, Djura PJ, Mahendron M, Tapiolas DM (1983) Studies of Australian soft corals. XXXI. Novel furanosesquiterpenes from several sinularian soft corals (Coelenterata, Octocorallia, Alcyonacea). Aust J Chem 36:371–376

    Article  CAS  Google Scholar 

  13. Anjaneyulu ASR, Krishnamurthy MVR, Rao GV (1997) Rare aromadendrane diterpenoids from a new soft coral species of Sinularia genus of the Indian Ocean. Tetrahedron 53:9301–9312. doi:10.1016/S0040-4020(97)00584-X

    Article  CAS  Google Scholar 

  14. Faulkner DJ (2001) Marine natural products. Nat Prod Rep 18:1–49. doi:10.1039/b006897g

    Article  CAS  PubMed  Google Scholar 

  15. Goud TV, Reddy NS, Krishnaiah P, Venkateswarlu Y (2002) Spathulenol: a rare sesquiterpene from soft coral Sinularia kavarattiensis. Biochem Syst Ecol 30:493–495. doi:10.1016/S0305-1978(01)00094-1

    Article  Google Scholar 

  16. Venkateswarlu Y, Sridevi KV, Rama Rao M (1999) New Furanocembranoid Diterpenes from the soft coral Sinularia maxima. J Nat Prod 62:756–758. doi:10.1021/np9804076

    Article  CAS  PubMed  Google Scholar 

  17. Jin P, Deng Z, Pei Y, Fu H, Li J, Ofwegen LV, Proksch P, Lin W (2005) Polyhydroxylated steroids from the soft coral Sinularia dissecta. Steroids 70:487–493. doi:10.1016/j.steroids.2005.01.001

    Article  CAS  PubMed  Google Scholar 

  18. Spivey AC, Weston M, Woohead S (2002) Celastraceae sesquiterpenoids: biological activity and synthesis. Chem Soc Rev 31:43–59. doi:10.1039/b000678p

    Article  CAS  PubMed  Google Scholar 

  19. Ojika M, Islam MK, Shintani T, Zhang Y, Okamoto T, Sakagami Y (2003) Three new cytotoxic acylspermidines from the soft coral, Sinularia sp. Biosci Biotechnol Biochem 67:1410–1412. doi:10.1271/bbb.67.1410

    Article  CAS  PubMed  Google Scholar 

  20. Das B, Reddy SV, Krishnaiah M, Sharma AVS, Ravi Kumar K, Venkateswara Rao J, Sridhar V (2007) Acetylated pseudoguaianolides from Parthenium hysterophorus and their cytotoxic activity. Phytochemistry 68:2029–2034. doi:10.1016/j.phytochem.2007.05.002

    Article  CAS  PubMed  Google Scholar 

  21. Chandrika PM, Yakaiah T, Raghu Ram Rao A, Narsaiah B, Chakra Reddy N, Sridhar V, Venkateshwara Rao J (2008) Synthesis of novel 4, 6-disubstituted quinazoline derivatives, their anti-inflammatory and anti-cancer activity (cytotoxic) against U937 leukemia cell lines. Eur J Med Chem 43:846–852. doi:10.1016/j.ejmech.2007.06.010

    Article  CAS  PubMed  Google Scholar 

  22. Coll JC, Mitchell SJ, Stokie GJ (1977) Studies of Australian soft corals. V. Novel furanosesquiterpene acid from soft coral sinularia-gonatodes (kolonko). Tetrahedron Lett 18:1539–1542. doi:10.1016/S0040-4039(01)93097-7

    Article  Google Scholar 

  23. Anjaneyulu ASR, Rao GV, Rao NSK (1996) Sesqui and diterpenoids of the soft coral Sinularia hirta of the Andaman and Nicobar Island. Indian J Chem 35:815–818

    Google Scholar 

  24. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi:10.1016/0022-1759(83)90303-4

    Article  CAS  PubMed  Google Scholar 

  25. Baskic D, Popovic S, Ristic P, Arsenijevic NN (2006) Analysis of cycloheximideinduced apoptosis in human leukocytes: fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide. Cell Biol Int 30:924–932. doi:10.1016/j.cellbi.2006.06.016

    Article  CAS  PubMed  Google Scholar 

  26. Pan MH, Chang WL, Lin-Shiau SY, Ho CT, Lin JK (2001) Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. J Agric Food Chem 49:1464–1474. doi:10.1021/jf001129v

    Article  CAS  PubMed  Google Scholar 

  27. Schyschka L, Rudy A, Jeremias I, Barth N, Pettit GR, Vollmar AM (2008) Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP. Leukemia 22:1737–1745. doi:10.1038/leu.2008.146

    Article  CAS  PubMed  Google Scholar 

  28. Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, Sironi M, Jimeno J, Faircloth GT, Giavazzi R, d’Incalci M (2003) Aplidine a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia 17:52–59. doi:10.1038/sj.leu.2402788

    Article  CAS  PubMed  Google Scholar 

  29. Pettersson F, Colston KW, Dalgleish AG (2000) Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro. Br J Cancer 83:239–245. doi:10.1054/bjoc.2000.1281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tamatani T, Azuma M, Motegi K, Takamaru N, Kawashima Y, Bando T (2007) Cepharanthin-enhanced radiosensitivity through the inhibition of radiation-induced nuclear factor-kappaB activity in human oral squamous cell carcinoma cells. Int J Oncol 31:761–768

    CAS  PubMed  Google Scholar 

  31. Miyauchi S, Moroyama T, Kyoizumi S, Asakawa J, Okamoto T, Takada K (1988) Malignant tumor cell lines produce interleukin-1-like factor. In Vitro Cell Dev Biol 24:753–758. doi:10.1007/BF02623644

    Article  CAS  PubMed  Google Scholar 

  32. Lopéz L, Villavicencio MA, Albores A, Martínez M, de la Garza J, Meléndez-Zajgla J, Maldonado V (2002) Cupressus lusitanica (Cupressaceae) leaf extract induces apoptosis in cancer cells. J Ethnopharmacol 80:115–120. doi:10.1016/S0378-8741(01)00417-2

    Article  PubMed  Google Scholar 

  33. Nojima H (1997) Cell cycle checkpoints, chromosome stability, and the progression of cancer. Hum Cell 10:221–230

    CAS  PubMed  Google Scholar 

  34. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC (1994) Cleavage of poly (ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346–347. doi:10.1038/371346a0

    Article  CAS  PubMed  Google Scholar 

  35. Chan SL, Yu VC (2004) Proteins of the Bcl-2 family in apoptosis signaling: from mechanistic insights to therapeutic opportunities. Clin Exp Pharmacol Physiol 31:119–128. doi:10.1111/j.1440-1681.2004.03975.x

    Article  CAS  PubMed  Google Scholar 

  36. Jacobson MD, Raff MC (1995) Programmed cell death and Bcl-2 protection in very low oxygen. Nature 374:814–816. doi:10.1038/374814a0

    Article  CAS  PubMed  Google Scholar 

  37. Renz A, Berdel WE, Kreuter M, Belka C, Schulze-Osthoff K, Los M (2001) Rapid extracellular release of cytochrome c is specific extracellular release of cytochrome c is specific for apoptosis and marks cell death in vivo. Blood 98:1542–1548. doi:10.1182/blood.V98.5.1542

    Article  CAS  PubMed  Google Scholar 

  38. Costantini P, Jacotot E, Decaudin D, Kroemer G (2000) Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 92:1042–1053. doi:10.1093/jnci/92.13.1042

    Article  CAS  PubMed  Google Scholar 

  39. Sancho P, Troyano A, Fernandez C, De Blas E, Aller P (2003) Differential effects of catalase on apoptosis induction in human promonocytic cells. Relationships with heatshock protein expression. Mol Pharmacol 63:581–589. doi:10.1124/mol.63.3.581

    Article  CAS  PubMed  Google Scholar 

  40. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, DiPietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (2001) In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61:1013–1021

    CAS  PubMed  Google Scholar 

  41. Hood KA, West LM, Rouwe B, Northcote PT, Berridge MV, Wakefield SJ, Miller JH (2002) Peloruside A, a novel antimitotic agent with paclitaxel-like microtubule stabilizing activity. Cancer Res 62:3356–3360

    CAS  PubMed  Google Scholar 

  42. Zuco V, Supino R, Righetti SC, Cleris L, Marchesi E, Passerine Gambacorti C, Formelli F (2002) Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett 175:17–25. doi:10.1016/S0304-3835(01)00718-2

    Article  CAS  PubMed  Google Scholar 

  43. Anazetti MC, Melo PS, Duran N, Haun M (2003) Comparative cytotoxicity of dimethylamide-crotonin in the promyelocytic leukemia cell line (HL60) and human peripheral blood mononuclear cells. Toxicology 188:261–274

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are thankful to the Directors of Indian Institute of Chemical Technology (IICT) and Centre for Cellular and Molecular Biology (CCMB), Hyderabad for providing the facilities and constant encouragement throughout the study. S. K. Arepalli, and V. Sridhar are also thankful to Council of Scientific and Industrial Research (CSIR), Govt. of India, New Delhi for the grant of senior research fellowship.

Author information

Authors and Affiliations

  1. Toxicology Unit, Biology Division, Indian Institute of Chemical Technology, Hyderabad, 500 607, India

    S. K. Arepalli, V. Sridhar & J. Venkateswara Rao

  2. Flow-Cytometry Facility, Centre for Cellular and Molecular Biology, Hyderabad, 500 007, India

    P. Kavin Kennady

  3. Natural Products Laboratory, Organic Division-I, Indian Institute of Chemical Technology, Hyderabad, 500 607, India

    Y. Venkateswarlu

Authors
  1. S. K. Arepalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Sridhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Venkateswara Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Kavin Kennady
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Venkateswarlu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Venkateswara Rao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arepalli, S.K., Sridhar, V., Venkateswara Rao, J. et al. Furano-sesquiterpene from soft coral, Sinularia kavarittiensis: induces apoptosis via the mitochondrial-mediated caspase-dependent pathway in THP-1, leukemia cell line. Apoptosis 14, 729–740 (2009). https://doi.org/10.1007/s10495-009-0332-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-009-0332-z

Keywords

Search

Navigation