Sensitization of human Ewing's tumor cells to chemotherapy and heat treatment by the bioflavonoid quercetin

Anticancer Res. Jul-Aug 2003;23(4):3359-66.

Abstract

Background: The bioflavonoid quercetin, a polyphenolic compound widely distributed in the plant kingdom, has been demonstrated to exert cytostatic activity against a variety of tumor cells in vitro and in vivo. It may be useful in cancer therapy as a thermosensitizer by increasing the cell killing effect of hyperthermia and chemotherapy because of its ability to suppress heat-shock protein expression.

Materials and methods: We investigated the effect of quercetin combined with two cytotoxic agents, cDDP (cis-diamminedichloroplatinum II) and VP-16 (etoposide), under various heat-shock conditions in two Ewing's tumor cell lines SK-ES-1 and RD-ES, using XTT-assay and Western blot analysis.

Results: Induction of thermotolerance by a sublethal heat-shock (42 degrees C, 1 hour) led to a transient resistance against subsequent heat treatment alone or combined thermochemotherapy with the crosslinking agent cDDP or the topoisomerase II inhibitor VP-16. Quercetin (> or = 50 microM) applied for 24 hours inhibited cell proliferation, increased the cytotoxic activity of cDDP or VP-16 alone or combined with simultaneous hyperthermia and suppressed the development of thermotolerance. Hyperthermia (43 degrees C, 45 degrees C for 1 hour) induced high expression of the inducible form of HSP70, whereas HSP27, which is constitutively expressed at normothermic conditions, is only slightly induced by 43 degrees C and nearly completely suppressed at 45 degrees C. Induction of thermotolerance is accompanied by an elevated expression of both HSP70 and HSP27. Quercetin (> or = 50 microM), alone as well as in combination with thermochemotherapy, inhibited the expression of both HSP70 and HSP27.

Conclusion: These data suggest that the bioflavonoid quercetin potentially may be useful in clinical trials for optimizing the efficacy of hyperthermia in combination with chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cisplatin / administration & dosage
  • Combined Modality Therapy
  • Drug Synergism
  • Etoposide / administration & dosage
  • HSP27 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins*
  • Humans
  • Hyperthermia, Induced*
  • Molecular Chaperones
  • Neoplasm Proteins / biosynthesis
  • Quercetin / administration & dosage
  • Quercetin / pharmacology*
  • Sarcoma, Ewing / drug therapy
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / therapy*
  • Tumor Cells, Cultured

Substances

  • HSP27 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Neoplasm Proteins
  • Etoposide
  • Quercetin
  • Cisplatin