Heat- and 4-hydroperoxy-ifosfamide-induced apoptosis in B cell precursor leukaemias

Abstract

In the group of high risk childhood acute lymphoblastic leukaemia (ALL), very early and early relapses have a very poor prognosis with conventional chemotherapy alone. Remission induction in these patients is often hindered by drug resistance. Thus, intensifying chemotherapy strategies are required. Application of hyperthermia enhances efficacy of certain anti-neoplastic drugs such as ifosfamide. In this study, effects and molecular mechanisms of ifosfamide - and hyperthermia-induced apoptosis are investigated in a B cell precursor leukaemia cell line (REH) and in primary patient-derived B cell progenitor leukaemic blasts. Both 4OOH-IFA and hyperthermia are able to induce cell death in leukaemic cells, mainly by induction of caspase-dependent apoptosis. However, completely different kinetics of caspase-3, -8 and -9 activation are found for both stimuli. In addition, activation of caspase-1 is only observed following stimulation with hyperthermia. Combined application of ifosfamide and hyperthermia reveals increased cytotoxicity in both the leukaemia cell line and in 5/8 of the patient-derived leukaemic blast samples. In conclusion, hyperthermia and ifosfamide mediate cytotoxicity in B precursor leukaemic blasts by different kinetics of caspase activation. This might explain the additive effects of 4OOH-IFA and heat on leukaemic cell death. Therefore, whole body thermochemotherapy could be considered as a treatment option in relapsed leukaemic patients.

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

“…These responses were, in fact, closely linked temporally. Of note, our observation of caspase-9 activation with febrile hyperthermia appears unique, as numerous other studies have used acute levels of hyperthermia [Enomoto et al, 2001;Little and Mirkes, 2002;Choi et al, 2003;Mauz-Korholz et al, 2003;Zhang et al, 2003;Souslova and Averill-Bates, 2004;Yasumoto et al, 2004]. In contrast to the role we have defined for caspase activation in this MCF-7 model, the anti-oxidant BHA was without effect on TNF killing, with or without hyperthermia ( Fig.…”

The influence of temperature on antiproliferative effects, cellular uptake and DNA platination of the clinically employed Pt(II)-drugs

“…At a first glance, cisplatin shows the greatest enhancement in cell killing with heat among platinum(II) complexes [25,28,31,32]. Increased drug accumulation by hyperthermia is one of the mechanisms involved in increased cisplatin toxicity and induced apoptosis in many human tumour types [29,35,36].…”

Whole body thermochemotherapy in an infant with rhabdomyosarcoma and pulmonary metastases

“…Experimental investigations demonstrated that hyperthermia enhances the efficacy of chemotherapy. This enhancement was shown to be mediated by different apoptotic signaling pathways in tumor cells [6,7]. Our patient tolerated the above described therapy regimen well, although she was of very young age and presented with extensive pulmonary metastases.…”

“…Multiple studies have attempted to answer this question with conflicting results. Several series have described a worse prognosis for those who are younger at the time of diagnosis (under the ages of 10, 12, or 15 years) [1][2][3][4][5][6]. Other investigators have reported equivalent rates of survival between younger patients with osteosarcoma and patients who are in adolescence or young adulthood [7][8][9][10][11][12][13][14][15][16].…”