• Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines.

      Wang, Weiguang; McLeod, Howard; Cassidy, James (Wiley InterScience, 2003)
      5-Fluorouracil (5-FU) is the major chemotherapeutic component for colorectal cancer (CRC) and other types of solid tumours. Resistance of cancer cells to 5-FU is considered the major obstacle for successful chemotherapy. NF-kappaB is a transcription factor. Cancer cells with high NF-kappaB nuclear activity demonstrate robust chemo- and radio-resistance. We demonstrated that nuclear NF-kappaB activity in CRC cell lines, DLD-1 and RKO(WT), was significantly induced by 5-FU in a concentration- and time-dependent manner. 5-FU induced IkappaBalpha degradation and promoted both NF-kappaB nuclear translocation and its DNA binding activity. 5-FU treatment did not influence the activities of AP-1, AP-2, Oct-1, SP-1, CRE-B and TFIID. Disulfiram (DS), a clinically used anti-alcoholism drug, strongly inhibited constitutive and 5-FU-induced NF-kappaB activity in a dose-dependent manner. DS inhibited both NF-kappaB nuclear translocation and DNA binding activity but had no effect on 5-FU-induced IkappaBalpha degradation. Used in combination, DS significantly enhanced the apoptotic effect of 5-FU on DLD-1 and RKO(WT) cell lines and synergistically potentiated the cytotoxicity of 5-FU to both cell lines. DS also effectively abolished 5-FU chemoresistance in a 5-FU resistant cell line H630(5-FU) in vitro. As DS has extensive preclinical and clinical experience, translating its anticancer usage from in vitro study to clinical trials is relatively straightforward.
    • Down-regulation of nitric oxide production by droloxifene and toremifene in human breast cancer cells.

      Martin, Jan H.; Symonds, A.; Chohan, S. (Spandidos Publications Ltd, 2003)
      We investigated the effect of tamoxifen, 4-OH tamoxifen, toremifene droloxifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination, for their effect on nitric oxide production by MCF-7 and ZR-75-1 human breast cancer cells. Tamoxifen and 4-OH tamoxifen singly had no effect on nitric oxide production by either cell line. However, treatment with droloxifene or toremifene significantly reduced nitric oxide production by both MCF-7 and ZR-75-1 human breast cancer cell lines. Combination treatment with anti-estrogens and interferon-alpha2a interferon-alpha2b or interferon-alpha2c had no synergistic or additive effect compared to each drug singly.
    • Synergistic antitumour effect of a combination of toremifene and interferon-alpha on ZR-75-1 human breast cancer cells: dependence on interferon-alpha subtype.

      Martin, Jan H.; Symonds, A. (Spandidos Publications Ltd, 2002)
      We investigated the effect of toremifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination for their effect on the growth of ZR-75-1 human breast cancer cells. Median effect analysis was used to determine synergistic or additive effects. Anti-proliferative studies showed that the growth of ZR-75-1 cells was inhibited to a greater extent by combination treatment with toremifene plus interferon-alpha2a, resulting in a synergistic interaction (CI <1) for all concentrations tested. A combination of toremifene plus interferon-alpha2b resulted in a synergistic interaction (CI <1) for the two highest concentrations of toremifene (10(-6) and 10(-7) M) and an additive effect (CI approximately equal to 1) for the lower concentrations (10(-8) to 10(-10) M). When toremifene was combined with interferon-alpha2c no additive or synergistic interaction was determined.