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Updated: Jun 16, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
ATP sensitizes H460 lung carcinoma cells to cisplatin-induced apoptosis
Els L R Swennen1, Vanessa Ummels, Irina Buss
1Department of Epidemiology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre Maastricht, The Netherlands. e.swennen@farmaco.unimaas.nl <e.swennen@farmaco.unimaas.nl>
Abstract:
Platinum resistance of cancer cells may evolve due to a decrease in intracellular drug accumulation, decreased cell permeability or by an increased deactivation of the drug by glutathione (GSH). The aim of this study was (1) to investigate the effect of adenosine 5'-triphosphate (ATP) on the cytotoxicity of cisplatin in a large cell lung carcinoma cell line (H460), and (2) to examine the potential involvement of increased cisplatin uptake, GSH depletion and pyrimidine starvation by ATP in this effect. H460 cells were harvested and seeded (5% CO(2); 37 degrees C). Subsequently, cells were incubated with medium or ATP followed by an incubation with cisplatin. Cytotoxicity screening was analyzed by the sulforhodamine B (SRB) colorimetric assay, lactate dehydrogenase and caspase-3/7 activity. Pre-incubation for 72h with 0.3 and 3mM ATP strongly enhanced the anti-proliferative potency of cisplatin 2.9- and 7.6-fold, respectively. Moreover, after incubation of H460 cells with 0.3mM ATP the intracellular platinum concentration increased, indicating increased cisplatin uptake by ATP. ATP, despite lowering the LD(50) of cisplatin, did not modulate GSH levels in H460 cells. ATP itself showed a biphasic effect on H460 cell growth: 0.3mM inhibited H460 cell growth via the pyrimidine starvation effect, activation of caspase-3/7 and LDH leakage, while 3mM ATP showed no effect on cell growth. In conclusion, ATP sensitizes the H460 cells to cisplatin-induced apoptosis. The effect of 0.3mM ATP is not due to GSH depletion but involves increased cisplatin uptake and pyrimidine starvation due to ATP conversion to adenosine followed by cellular uptake.
Insights
Adenosine 5'-triphosphate (ATP) enhances cisplatin
Area of Science:
- Oncology
- Cancer Cell Biology
- Pharmacology
Background:
- Platinum-based chemotherapy resistance in cancer cells is a significant clinical challenge.
- Mechanisms of resistance include reduced drug uptake, decreased permeability, and increased drug inactivation by glutathione (GSH).
- Understanding modulators of platinum drug efficacy is crucial for overcoming resistance.
Purpose of the Study:
- To investigate the impact of adenosine 5 '-triphosphate (ATP) on cisplatin cytotoxicity in H460 large cell lung carcinoma cells.
- To explore the roles of increased cisplatin uptake, GSH depletion, and pyrimidine starvation in ATP's effect.
- To elucidate the mechanisms by which ATP influences platinum drug response.
Main Methods:
- H460 cells were cultured and pre-incubated with varying concentrations of ATP (0.3mM and 3mM) or medium.
- Cells were subsequently treated with cisplatin.
- Cytotoxicity was assessed using sulforhodamine B (SRB) assay, lactate dehydrogenase (LDH) leakage, and caspase-3/7 activity assays.
Main Results:
- Pre-incubation with 0.3mM and 3mM ATP significantly enhanced cisplatin's anti-proliferative effects by 2.9- and 7.6-fold, respectively.
- ATP (0.3mM) increased intracellular platinum concentration, indicating enhanced cisplatin uptake.
- ATP did not alter GSH levels but induced pyrimidine starvation, caspase-3/7 activation, and LDH leakage at 0.3mM, suggesting a role in sensitization.
Conclusions:
- Adenosine 5 '-triphosphate (ATP) sensitizes H460 lung cancer cells to cisplatin-induced apoptosis.
- The sensitizing effect at 0.3mM ATP is mediated by increased cisplatin uptake and pyrimidine starvation, not GSH depletion.
- ATP's effects involve its conversion to adenosine, subsequent cellular uptake, and downstream signaling pathways.
