NF-kappa B activation in vivo in both host and tumour cells by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a new anticancer agent developed in this centre, has an antivascular action and causes regression of transplantable murine tumours that is mediated partially by the intratumoral production of tumour necrosis factor (TNF). DMXAA activates the nuclear factor-kappaB (NF-kappaB) transcription factor, which is involved in TNF synthesis and has also been suggested to mediate resistance to TNF. We wished to determine whether tumour cell NF-kappaB activation modulated the in vitro and in vivo effects of DMXAA. We compared the response of the 70Z/3 pre-B lymphoma cell line with that of its mutant 1.3E2 sub-line, which has a defective gamma-subunit of IKK, the kinase that phosphorylates IkappaB leading to NF-kappaB activation. As shown by electrophoretic mobility shift assays (EMSAs), DMXAA induced in vitro translocation of NF-kappaB (p50 and p65 subunits) into the nucleus of 70Z/3 cells, but not of 1.3E2 cells. However, when the cell lines were then grown as subcutaneous tumours in mice and treated with DMXAA (25 mg/kg), activation of NF-kappaB was found in nuclear extracts prepared from both 70/Z3 and 1.3E2 tumours, as well as from Colon 38 tumours that were used for comparison. This suggests that DMXAA induces NF-kappaB responses in host components of the tumour. Tumours grown from both 70Z/3 and 1.3E2 cells were found to regress completely following DMXAA treatment. Thus, the antitumour action of DMXAA appears to be independent of the ability of the target tumour cell population to induce NF-kappaB expression. Moreover, activation of NF-kappaB in the tumour cell did not confer resistance to DMXAA-induced therapy.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, Auckland University, Private Bay 92019, New Zealand.
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ST
Woon
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Zwain
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Schooltink
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Newth
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Baguley
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Ching
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured; D014966:Xanthenes / Q000494:pharmacology / Q000627:therapeutic use*; D044004:Xanthones
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016328:NF-kappa B; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan