Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy

Mol Cancer Ther. 2003 Dec;2(12):1361-8.

Abstract

The incidence of non-Hodgkin's lymphoma (NHL) has been increasing and is now the leading cause of death in males aged 15-54. Diffuse large cell lymphoma (DLCL) is the most common subtype of NHL. These cells are notable for the high expression of the transcription factor nuclear factor kappa beta (NF-kappaB), raising the possibility that constitutive activation of the NF-kappaB pathway may contribute to the poor prognosis of DLCL patients. Soy isoflavone genistein promotes apoptosis by decreasing NF-kappaB activity. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the standard therapy for DLCL with a cure rate of approximately 40%. The WSU-DLCL(2) cell line and its severe combined immunodeficient (SCID) xenograft have constitutively active NF-kappaB which provides us with an excellent model in which to study NF-kappaB modulation and CHOP sensitization by genistein. The antitumor activity of CHOP with or without a genistein was evaluated in our WSU-DLCL(2) model. In vivo, WSU-DLCL(2)-bearing SCID mice received genistein alone (800 micro g kg(-1) day(-1), p.o. as gavages for 5 days), CHOP alone ("C", 40 mg/kg, i.v.; "H", 3.3 mg/kg, i.v.; "O", 0.5 mg/kg, i.v.; and "P", 0.2 mg/kg, every day for 5 days, p.o.), or genistein for 5 days followed by CHOP. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log(10) kill for genistein, CHOP, and genistein followed by CHOP were 33.6%, 19.2%, and 5.2%; 7, 8, and 17 days; and 1.0, 1.2, and 2.6, respectively. To begin elucidating the mechanism of genistein-induced sensitization of WSU-DLCL(2) cells to CHOP chemotherapy in this xenograft mouse model, we studied the in vitro effect of genistein on WSU-DLCL(2) growth inhibition, cell cycle, Bax:Bcl-2 ratio, NF-kappaB DNA binding, and apoptosis in vitro. At 30 micro M, genistein inhibited the growth significantly, induced G(2)-M arrest, increased Bax:Bcl-2 ratio, decreased NF-kappaB DNA binding, and induced apoptosis. Genistein also inhibited NF-kappaB DNA binding in vivo, whereas CHOP enhanced it. Our results show that genistein has growth modulatory effects on WSU-DLCL(2) cells and enhances the antitumor activity of CHOP. Because soy isoflavone genistein is a widely available nutritional supplement, its use in combination with CHOP chemotherapy should be further explored in a clinical trial in patients with NHL.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cyclophosphamide / administration & dosage
  • DNA, Neoplasm / metabolism
  • Doxorubicin / administration & dosage
  • G2 Phase / drug effects
  • Genistein / pharmacology*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Mice
  • Mice, SCID
  • Mitosis / drug effects
  • NF-kappa B / metabolism
  • Prednisone / administration & dosage
  • Vincristine / administration & dosage

Substances

  • DNA, Neoplasm
  • NF-kappa B
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • Genistein
  • Prednisone

Supplementary concepts

  • CHOP protocol