| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | Frontiers in Pharmacology | ||||
| Publisher: | Frontiers | ||||
| Place of Publication: | LAUSANNE | ||||
| Volume: | 9 | ||||
| Date: | 2018 | ||||
| Institutions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) | ||||
| Identification Number: |
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| Keywords: | STRESS-INDUCED APOPTOSIS; METRONOMIC CHEMOTHERAPY; NUCLEAR VESICULATION; POSSIBLE INVOLVEMENT; LEUKEMIA-CELLS; STEM-CELLS; CANCER; THERAPY; ACTIVATION; INDUCTION; apoptosis; caspase-3; caspase-2; metronomic chemotherapy; AML; differentiation | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 46602 |
Web of ScienceAbstract
Cytotoxic chemotherapy, still the most widely adopted anticancer treatment, aims at eliminating cancer cells inducing apoptosis with DNA damaging agents, exploiting the differential replication rate of cancer vs. normal cells; efficiency is evaluated in terms of extent of induced apoptosis, which depends on the individual cell sensitivity to a given drug, and on the dose. In this in vitro study, ...
Abstract
Cytotoxic chemotherapy, still the most widely adopted anticancer treatment, aims at eliminating cancer cells inducing apoptosis with DNA damaging agents, exploiting the differential replication rate of cancer vs. normal cells; efficiency is evaluated in terms of extent of induced apoptosis, which depends on the individual cell sensitivity to a given drug, and on the dose. In this in vitro study, we report that the concentration of etoposide, a topoisomerase II poison widely used in clinics, determines both the kinetics of cell death, and the type of apoptosis induced. We observed that on a set of myeloid leukemia cell lines, etoposide at high (50 uM) dose promoted a rapid caspase-3-mediated apoptosis, whereas at low (0.5 uM) dose, it induced morphological and functional granulocytic differentiation and caspase-2-dependent, but caspase-3-independent, cell death, displaying features consistent with apoptosis. Both differentiation and caspase-2- (but not 3)-mediated apoptosis were contrasted by caffeine, a well-known inhibitor of the cellular DNA damage response (DDR), which maintained cell viability and cycling, indicating that the effects of low etoposide dose are not the immediate consequence of damage, but the result of a signaling pathway. DDR may be thus the mediator responsible for translating a mere dosage-effect into different signal transduction pathways, highlighting a strategic action in regulating timing and mode of cell death according to the severity of induced damage. The evidence of different molecular pathways induced by high vs. low drug doses may possibly contribute to explain the different effects of cytotoxic vs. metronomic therapy, the latter achieving durable clinical responses by treating cancer patients with stable, low doses of otherwise canonical cytotoxic drugs; intriguingly caspase-3, a major promoter of wounded tissue regeneration, is also a key factor of post-therapy cancer repopulation. All this suggests that cancer control in response to cytotoxic drugs arises from complex reprogramming mechanisms in tumor tissue, recently described as anakoinosis.
Metadata last modified: 28 Jul 2021 16:58
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