title: Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.
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.
authors.affiliation: Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. Mohammad@karmanos.org
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: Ayad
authors.initials: A
authors.lastname: Al-Katib
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Fazlul
authors.initials: F
authors.lastname: Sarkar
authors.forename: Omer
authors.initials: O
authors.lastname: Kucuk
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D004273:DNA, Neoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D016195:G2 Phase / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D011241:Prednisone / Q000008:administration & dosage; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D004273:DNA, Neoplasm; D016328:NF-kappa B; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D019833:Genistein; D011241:Prednisone