Skip to main content
SpringerLink
Log in

Enhancement of hyperthermia-induced apoptosis by a new synthesized class of furan-fused tetracyclic compounds

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

Abstract

The combined effects of hyperthermia (44°C, 20 min) or X-rays (10 Gy) and a new class of furan-fused tetracyclic synthesized compounds (DFs), on apoptosis in human lymphoma U937 cells were investigated. Among the tested compounds (DF1∼6), the combined treatment of 10 μM DF with TIPS (triisopropylsilyloxy) (Designated #3 DF3) and hyperthermia showed the largest potency to induce DNA fragmentation at 6 h after hyperthermia but no enhancement was observed if it was combined with X-rays. Enhancement of hyperthermia-induced apoptosis by DF3 in a dose-dependent manner was observed. When the cells were treated first with DF3 at a nontoxic concentration of 20 μM, and exposed to hyperthermia afterwards, a significant enhancement of heat-induced apoptosis was evidenced by DNA fragmentation, morphological changes and phosphatidylserine externalization. The activation of Bid, but no change of Bax and Bcl-2 were observed after the combined treatment. The release of cytochrome c from mitochondria to cytosol, which was induced by hyperthermia, was enhanced by DF3. Mitochondrial transmembrane potential was decreased and the activation of caspase-3 and caspase-8 was enhanced in the cells treated with the combination. Externalization of Fas was observed following the combined treatment. Flow cytometry revealed rapid and sustained increase of intracellular superoxide due to DF3, and showed subsequent and transient increase in the formation of intracellular hydrogen peroxide (H2O2), which was further increased when hyperthermia was combined. These results indicate that the intracellular superoxide and H2O2 generated by DF3 enhance the hyperthermia-induced apoptosis via the Fas-mediated mitochondrial caspase-dependent pathway.

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
Fig. 9

Similar content being viewed by others

References

  1. Lee RH, Slate DL, Moretti R, Alvi KA, Crews P (1992) Marine sponge polyketide inhibitors of protein tyrosine kinase. Biochem Biophys Res Commun 184:765–772

    Article  PubMed  CAS  Google Scholar 

  2. Roll DM, Scheuer PJ, Matsumoto GK, Clardy J (1983) Halenaquinone, a pentacyclic polyketide from a marine sponge. J Am Chem Soc 105:6177–6178

    Article  CAS  Google Scholar 

  3. Schmitz FJ, Bloor SJ (1988) Xesto- and halenaquinone derivatives from a sponge, Adocia sp., from truk lagoon. J Org Chem 53:3922–3925

    Article  CAS  Google Scholar 

  4. Fujiwara H, Matsunaga K, Saito M et al (2001) Halenaquinone, a novel phosphatidylinositol 3-kinase inhibitor from a marine sponge, induces apoptosis in PC12 cells. Eur J Pharmacol 413:37–45

    Article  PubMed  CAS  Google Scholar 

  5. Matsuya Y, Sasaki K, Nagaoka M et al (2004) Synthesis of a new class of furan-fused tetracyclic compounds using o-quinodimethane chemistry and investigation of their antiviral activity. J Org Chem 69:7989–7993

    Article  PubMed  CAS  Google Scholar 

  6. Harima Y, Nagata K, Harima K, Ostapenko VV, Tanaka Y, Sawada S (2001) A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma. Int J Hyperthermia 17:97–105

    Article  PubMed  CAS  Google Scholar 

  7. Overgaard J, Gonzalez Gonzalez D, Hulshof MC et al (1995) Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet 345:540–543

    Article  PubMed  CAS  Google Scholar 

  8. van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA (2000) Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 355:1119–1125

    Article  PubMed  Google Scholar 

  9. Vernon CC, Hand JW, Field SB et al (1996) Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys 35:731–744

    Article  PubMed  CAS  Google Scholar 

  10. Urano M, Kuroda M, Nishimura Y (1999) For the clinical application of thermochemotherapy given at mild temperatures. Int J Hyperthermia 15:79–107

    Article  PubMed  CAS  Google Scholar 

  11. Dahl O, Mella O (2002) Referee: hyperthermia alone or combined with cisplatin in addition to radiotherapy for advanced uterine cervical cancer. Int J Hyperthermia 18:25–30

    Article  PubMed  CAS  Google Scholar 

  12. Prosnitz L, Jones E (2002) Counterpoint: test the value of hyperthermia in patients with carcinoma of the cervix being treated with concurrent chemotherapy and radiation. Int J Hyperthermia 18:13–18

    Article  PubMed  CAS  Google Scholar 

  13. Szostak MJ, Kyprianou N (2000) Radiation-induced apoptosis: predictive and therapeutic significance in radiotherapy of prostate cancer (review). Oncol Rep 7:699–706

    PubMed  CAS  Google Scholar 

  14. Garzotto M, Haimovitz-Friedman A, Liao WC et al (1999) Reversal of radiation resistance in LNCaP cells by targeting apoptosis through ceramide synthase. Cancer Res 59:5194–5201

    PubMed  CAS  Google Scholar 

  15. Lin X, Zhang F, Bradbury CM et al (2003) 2-Deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is mediated via disruptions in thiol metabolism. Cancer Res 63:3413–3417

    PubMed  CAS  Google Scholar 

  16. Belka C, Jendrossek V, Pruschy M, Vink S, Verheij M, Budach W (2004) Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int J Radiat Oncol Biol Phys 58:542–554

    Article  PubMed  CAS  Google Scholar 

  17. Salganik RI (2001) The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr 20:464S-472S; discussion 473S–475S

    PubMed  CAS  Google Scholar 

  18. Shackelford RE, Kaufmann WK, Paules RS (2000) Oxidative stress and cell cycle checkpoint function. Free Radic Biol Med 28:1387–1404

    Article  PubMed  CAS  Google Scholar 

  19. Davidson JF, Whyte B, Bissinger PH, Schiestl RH (1996) Oxidative stress is involved in heat-induced cell death in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93:5116–5121

    Article  PubMed  CAS  Google Scholar 

  20. Flanagan SW, Moseley PL, Buettner GR (1998) Increased flux of free radicals in cells subjected to hyperthermia: detection by electron paramagnetic resonance spin trapping. FEBS Lett 431:285–286

    Article  PubMed  CAS  Google Scholar 

  21. Frank J, Kelleher DK, Pompella A, Thews O, Biesalski HK, Vaupel P (1998) Enhancement of oxidative cell injury and antitumor effects of localized 44 degrees C hyperthermia upon combination with respiratory hyperoxia and xanthine oxidase. Cancer Res 58:2693–2698

    PubMed  CAS  Google Scholar 

  22. Yoshikawa T, Kokura S, Tainaka K et al (1993) The role of active oxygen species and lipid peroxidation in the antitumor effect of hyperthermia. Cancer Res 53:2326–2329

    PubMed  CAS  Google Scholar 

  23. Arai Y, Kondo T, Tanabe K et al (2002) Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells. J Biol Chem 277:18986–18993

    Article  PubMed  CAS  Google Scholar 

  24. Cui ZG, Kondo T, Matsumoto H (2006) Enhancement of apoptosis by nitric oxide released from alpha-phenyl-tert-butyl nitrone under hyperthermic conditions. J Cell Physiol 206:468–476

    Article  PubMed  CAS  Google Scholar 

  25. Li FJ, Kondo T, Zhao QL et al (2001) Enhancement of hyperthermia-induced apoptosis by a free radical initiator, 2,2′-azobis (2-amidinopropane) dihydrochloride, in human histiocytic lymphoma U937 cells. Free Radic Res 35:281–299

    Article  PubMed  CAS  Google Scholar 

  26. Yuki H, Kondo T, Zhao QL et al (2003) A free radical initiator, 2,2′-azobis (2-aminopropane) dihydrochloride enhances hyperthermia-induced apoptosis in human uterine cervical cancer cell lines. Free Radic Res 37:631–643

    Article  PubMed  CAS  Google Scholar 

  27. Zhao QL, Fujiwara Y, Kondo T (2006) Mechanism of cell death induction by nitroxide and hyperthermia. Free Radic Biol Med 40:1131–1143

    Article  PubMed  CAS  Google Scholar 

  28. Wada S, Cui ZG, Kondo T et al (2005) A hydrogen peroxide-generating agent, 6-formylpterin, enhances heat-induced apoptosis. Int J Hyperthermia 21:231–246

    PubMed  CAS  Google Scholar 

  29. Cui ZG, Kondo T, Ogawa R et al (2004) Enhancement of radiation-induced apoptosis by 6-formylpterin. Free Radic Res 38:363–373

    Article  PubMed  CAS  Google Scholar 

  30. Sellins KS, Cohen JJ (1987) Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol 139:3199–3206

    PubMed  CAS  Google Scholar 

  31. Hopcia KL, McCarey YL, Sylvester FC, Held KD (1996) Radiation-induced apoptosis in HL60 cells: oxygen effect, relationship between apoptosis and loss of clonogenicity, and dependence of time to apoptosis on radiation dose. Radiat Res 145:315–323

    Article  PubMed  CAS  Google Scholar 

  32. Zhao QL, Kondo T, Noda A, Fujiwara Y (1999) Mitochondrial and intracellular free-calcium regulation of radiation-induced apoptosis in human leukemic cells. Int J Radiat Biol 75:493–504

    Article  PubMed  CAS  Google Scholar 

  33. van Heerde WL, de Groot PG, Reutelingsperger CP (1995) The complexity of the phospholipid binding protein Annexin V. Thromb Haemost 73:172–179

    PubMed  Google Scholar 

  34. Datta R, Kojima H, Yoshida K, Kufe D (1997) Caspase-3-mediated cleavage of protein kinase C theta in induction of apoptosis. J Biol Chem 272:20317–20320

    Article  PubMed  CAS  Google Scholar 

  35. Gorman A, McGowan A, Cotter TG (1997) Role of peroxide and superoxide anion during tumour cell apoptosis. FEBS Lett 404:27–33

    Article  PubMed  CAS  Google Scholar 

  36. Royall JA, Ischiropoulos H (1993) Evaluation of 2′,7′-dichlorofluorescin and dihydrorhodamine 123 as fluorescent probes for intracellular H2O2 in cultured endothelial cells. Arch Biochem Biophys 302:348–355

    Article  PubMed  CAS  Google Scholar 

  37. Tsujimoto Y, Shimizu S (2000) Bcl-2 family: life-or-death switch. FEBS Lett 466:6–10

    Article  PubMed  CAS  Google Scholar 

  38. Katschinski DM, Boos K, Schindler SG, Fandrey J (2000) Pivotal role of reactive oxygen species as intracellular mediators of hyperthermia-induced apoptosis. J Biol Chem 275:21094–21098

    Article  PubMed  CAS  Google Scholar 

  39. Skibba JL, Quebbeman EJ, Kalbfleisch JH (1986) Nitrogen metabolism and lipid peroxidation during hyperthermic perfusion of human livers with cancer. Cancer Res 46:6000–6003

    PubMed  CAS  Google Scholar 

  40. Green DR (2000) Apoptotic pathways: paper wraps stone blunts scissors. Cell 102:1–4

    Article  PubMed  CAS  Google Scholar 

  41. Wang X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15:2922–2933

    PubMed  CAS  Google Scholar 

  42. Medema JP, Scaffidi C, Kischkel FC et al (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). Embo J 16:2794–2804

    Article  PubMed  CAS  Google Scholar 

  43. Nagata S (1997) Apoptosis by death factor. Cell 88:355–365

    Article  PubMed  CAS  Google Scholar 

  44. Scaffidi C, Medema JP, Krammer PH, Peter ME (1997) FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J Biol Chem 272:26953–26958

    Article  PubMed  CAS  Google Scholar 

  45. Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621

    Article  PubMed  CAS  Google Scholar 

  46. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    Article  PubMed  CAS  Google Scholar 

  47. Huang DC, Tschopp J, Strasser A (2000) Bcl-2 does not inhibit cell death induced by the physiological Fas ligand: implications for the existence of type I and type II cells. Cell Death Differ 7:754–755

    Article  PubMed  CAS  Google Scholar 

  48. Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20:929–935

    Article  PubMed  CAS  Google Scholar 

  49. Wei MC, Lindsten T, Mootha VK et al (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071

    PubMed  CAS  Google Scholar 

  50. Nitobe J, Yamaguchi S, Okuyama M et al (2003) Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes. Cardiovasc Res 57:119–128

    Article  PubMed  CAS  Google Scholar 

  51. Strasser A, Newton K (1999) FADD/MORT1, a signal transducer that can promote cell death or cell growth. Int J Biochem Cell Biol 31:533–537

    Article  PubMed  CAS  Google Scholar 

  52. Yin XM (2000) Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways. Cell Res 10:161–167

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan

    Da-Yong Yu, Qing-Li Zhao, Kanwal Ahmed, Zheng-Li Wei & Takashi Kondo

  2. Laboratory of Medicinal Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan

    Yuji Matsuya & Hideo Nemoto

Authors
  1. Da-Yong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuji Matsuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing-Li Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kanwal Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng-Li Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideo Nemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Kondo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, DY., Matsuya, Y., Zhao, QL. et al. Enhancement of hyperthermia-induced apoptosis by a new synthesized class of furan-fused tetracyclic compounds. Apoptosis 12, 1523–1532 (2007). https://doi.org/10.1007/s10495-007-0080-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-007-0080-x

Keywords

Search

Navigation