title: Reversal of tumor necrosis factor resistance in tumor cells by adriamycin via suppression of intracellular resistance factors.
abstract: Tumor necrosis factor (TNF) and various chemotherapeutic drugs show synergistic antitumor effects in vitro and in vivo, though the mechanism is not clear. Based on our previous finding that endogenous TNF (enTNF) acts as an intracellular resistance factor against exogenous TNF by scavenging oxygen free radicals (OFR) with induced manganous superoxide dismutase (MnSOD), we examined the suppression of these resistance factors by chemotherapeutic drugs and the resulting increase in TNF cytotoxicity. Pretreatment of HeLa cells, which produce an appreciable amount of enTNF and show apparent TNF resistance, with TNF followed by adriamycin (ADM) resulted in an additive effect, whereas pretreatment with ADM followed by TNF resulted in a synergistic effect. After treatment of HeLa cells with ADM, the expression of enTNF was remarkably suppressed and MnSOD activity was decreased by one-half. These results indicate that suppression of the intracellular resistance factors, i.e., enTNF and MnSOD, by ADM plays an important role in the mechanism of the synergistic antitumor effect of TNF in combination with ADM.
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine.
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
authors.forename: N
authors.initials: N
authors.lastname: Tsuji
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.forename: S
authors.initials: S
authors.lastname: Akiyama
authors.forename: D
authors.initials: D
authors.lastname: Kobayashi
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: N
authors.initials: N
authors.lastname: Yamauchi
authors.forename: Y
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D013482:Superoxide Dismutase