Pivotal Role of Reactive Oxygen Species as Intracellular Mediators of Hyperthermia-induced Apoptosis

Abstract

The effects of cellular antioxidant capacity on hyperthermia (HT)-induced apoptosis and production of antiapoptotic heat shock proteins (HSPs) were investigated in HL-60 cells and in HL-60AR cells that are characterized by an elevated endogenous catalase activity. Exposure of both cell lines to 43°C for 1 h initiated apoptosis. Apoptosis peaked at 3-6 h after heat exposure in the HL-60 cells. Whereas HL-60AR cells were partially protected against HT-induced apoptosis at these early time points, maximal levels of apoptosis were detected later, i.e. 12-18 h after heat exposure. This differential induction of apoptosis was directly correlated to the induction of the antiapoptotic HSP27 and HSP70. In particular, in the HL-60 cells HSP27 was significantly induced at 12-18 h after exposure to 43°C when apoptosis dropped. In contrast, coinciding with the late onset of apoptosis in HL-60AR cells at that time HL-60AR cells lacked a similar HSP response. In line with the higher antioxidant capacity HL-60AR cells accumulated reactive oxygen species to a lesser degree than HL-60 cells after heat treatment. Protection from HT-induced apoptosis as well as diminished heat-induced HSP27 expression was also observed after cotreatment of HL-60 cells with 43°C and catalase but not with superoxide dismutase. These data emphasize the pivotal role of reactive oxygen species for HT induced pro-and antiapoptotic pathways.

Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

“…In this respect, it has been demonstrated that in large tumor spheroids overexpressing P-glycoprotein low levels of ROS downregulated P-glycoprotein, whereas in small tumor spheroids, which are devoid of an MDR phenotype, oxidative stress induced upregulation of P-glycoprotein. 16,17 Heat incubation-induced oxidative stress has been recently reported for human T lymphocytes, 51 rat cardiomyocytes, 52 BC-8 macrophages 36, PC-3 prostate cancer cells 53 and HL-60 cells 24 ; however the source of ROS has not yet been identified. In our study hyperthermia treatment of tumor spheroids resulted in a robust increase of ROS presumably through the activity of an NADPH-oxidase, which has recently been demonstrated by us to be highly expressed in small tumor spheroids but downregulated with the induction of cell quiescence and MDR in large tumor spheroids.…”

“…[21][22][23] Hyperthermia-induced upregulation of P-glycoprotein may be associated to an elevation of intracellular ROS levels. Indeed it has been recently shown that hyperthermia increases generation of ROS in HL-60 cells 24 as well as in mice, 25 and it has been suggested that hyperthermia-induced ROS may play a role as signaling molecules that transduce the stress signal to the cell nucleus. Within the signaling cascade hyperthermia 26 as well as ROS 27 have been shown in a number of studies to activate MAPKs including ERK1,2, JNK, and p38.…”

Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway

“…Although controversial, ROS have been implicated as common mediators of apoptosis in a variety of cells, including neutrophils (15,37,38). In the present study, we used DPI, a flavoprotein inhibitor of NADPH oxidase (33), to address the possibility that ROS are involved in Mtb-induced apoptosis in neutrophils.…”

Impact of hyperthermic intraperitoneal chemotherapy on Hsp27 protein expression in serum of patients with peritoneal carcinomatosis

“…Unfortunately, the biological processes underlying resistance remain unknown. Hyperthermia improves the effectiveness of chemotherapy by creating oxygen free radicals, which activate signaling pathways leading to cell death, by oxidizing DNA, membrane lipids, and proteins (Katschinski et al 2000;Wang et al 2007).…”