Step-down heating enhances the cytotoxicity of human tumour necrosis factor on murine and human tumour cell linesin vitro

Abstract

The response of tumour necrosis factor (TNF)-sensitive murine L929 cells to TNF was enhanced approximately 1000-fold after step-down heating (SDH) for 30 min at a sensitizing temperature (ST) of 43 degrees C and a subsequent 24 h incubation at a test temperature (TT) of 40.5 degrees C, compared to continuous treatment at 37 degrees C. The TNF-resistant phenotype of murine EMT-6 mammary adenocarcinoma cells could be overcome by 24 h heating at a TT of 40.5 degrees C, and their sensitivity to TNF could be further increased by preheating at the ST for up to 60 min. The response of TNF-sensitive HCT-15 human colon adenocarcinoma cells was somewhat similar to that of L929 cells except that there was u approximately 2.5 log increase in TNF-sensitivity due solely to heating at 40.5 degrees C. The response of TNF-resistant DLD-1 human colon adenocarcinoma cells was similar to that of EMT-6 cells. In contrast, three normal cell lines demonstrated greater resistance to any TNF/SDH treatment examined. Our results suggest that SDH may overcome the resistance or enhance the response of tumour cells to TNF while minimizing cytotoxic effects on normal cells.

Hyperthermia engages the intrinsic apoptotic pathway by enhancing upstream caspase activation to overcome apoptotic resistance in MCF‐7 breast adenocarcinoma cells

“…Hyperthermia has been shown to potentiate TNF killing in vitro in certain TNF-sensitive models, such as L-M [Niitsu et al, 1988;Tsuji et al, 1992;Yamauchi et al, 1992;Watanabe et al, 1998], L929 [Klostergaard et al, 1989[Klostergaard et al, , 1996Tomasovic et al, 1989a,b;Leroux et al, 2001], and MCF-7 cells [Li and Oberley, 1997]. However, there is minimal experimental analysis of whether the combination of hyperthermia and TNF potentiates apoptotic or necrotic forms of cell death, or both, in any tumor model.…”

Febrile and acute hyperthermia enhance TNF‐induced necrosis of murine L929 fibrosarcoma cells via caspase‐regulated production of reactive oxygen intermediates

“…Since previous studies had indicated that both long duration (up to 24 h), febrile temperature (up to 40.5°C) hyperthermia, as well as short duration (1–2 h), acute temperature (up to 43–45°C) hyperthermia, could dramatically increase the death response of tumor cells to TNF in vitro as well as the anti‐tumor effect of TNF in vivo (Niitsu et al, 1988; Watanabe et al, 1988; Tomasovic et al, 1989a, 1989b; Tsuji et al, 1992; Klostergaard et al, 1989, 1996; Yamauchi et al, 1992; Li and Oberley, 1997), we undertook studies to determine how hyperthermia modulates the TNF‐dependent necrotic mechanism in L929 cells (Klostergaard et al, 1989, 1996; Tomasovic et al, 1989a, 1989b). Our results herein indicate that acute and particularly febrile hyperthermia principally amplify the afferent limb of the TNF response, namely, increased ROI production resulting in enhanced necrosis.…”

“…L929 cells, as well as other cell lines, demonstrate potentiation of TNF‐induced cytotoxicity by acute and febrile hyperthermia (Niitsu et al, 1988; Watanabe et al, 1988; Klostergaard et al, 1989, 1996; Tomasovic et al, 1989a, 1989b; Tsuji et al, 1992; Yamauichi et al, 1992; Li and Oberley, 1997); however, the molecular mechanism(s) of potentiation has only been minimally characterized. In the current study, we have examined this mechanism in L929 cells.…”