Related Experiment Video
Updated: Aug 7, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Impaired cisplatin influx in an A2780 mutant cell line: evidence for a putative, cis-configuration-specific, platinum
Jozien Helleman1, Herman Burger, Irene H L Hamelers
1Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Abstract:
The effectiveness of platinum drugs in the treatment of cancer is hindered by intrinsic and acquired resistance. The cause of clinical resistance to platinum compounds is still unknown. In an attempt to identify new cellular mechanisms of cisplatin resistance, a one-step cisplatin-selection procedure was used to generate resistant sublines of the platinum sensitive A2780 ovarian cancer cell line. In the present study we selected an A2780 subline, A2780-Pt, that has a significantly reduced ability to accumulate cisplatin (36% of the parent A2780 cell line) and consequently shows a clear cisplatin-resistant phenotype (resistance factor, i.e., RF: 8.6). The A2780-Pt cell line was specifically cross-resistant to carboplatin (RF: 12.0), tetraplatin (RF: 8.1) and oxaliplatin (RF: 6.1) which was associated with a reduced cellular platinum accumulation (50%, 54% and 58% of A2780, respectively). No cross-resistance was found for a variety of other anticancer agents. Further experiments to determine the cause of the platinum resistance of the A2780-Pt cell line revealed that: (1) impaired cellular platinum accumulation could not be attributed to aberrant expression of MRP2 (ABCC2), CTR1 (SLC31A1), ATP7A or ATP7B, (2) resistance was not associated with platinum inactivation by metallothionein and glutathione, (3) the platinum efflux rate was similar to that of A2780, (4) the defect in cellular accumulation and the resistance could be overcome by treatment with cisplatin nanocapsules, consistent with impaired influx, and (5) the defect in accumulation is specific for platinum compounds in the cis-configuration, since A2780-Pt cells did not show reduced accumulation of transplatin. This specificity suggests that not passive diffusion but an inward transporter is impaired in A2780-Pt. In conclusion, we generated an A2780 subline that showed a uniquely stable platinum resistance phenotype, which could theoretically be caused by an impaired inward transporter specific for cis-configurated platinum compounds.
Insights
Researchers developed cisplatin-resistant ovarian cancer cells (A2780-Pt) to study platinum drug resistance. This new cell line shows reduced platinum accumulation, offering insights into overcoming cancer treatment challenges.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Platinum-based chemotherapy is crucial for cancer treatment.
- Intrinsic and acquired resistance limit the effectiveness of platinum drugs.
- The precise mechanisms of clinical resistance to platinum compounds remain largely unknown.
Purpose of the Study:
- To investigate novel cellular mechanisms underlying cisplatin resistance.
- To generate and characterize a cisplatin-resistant ovarian cancer cell subline for mechanistic studies.
Main Methods:
- A one-step cisplatin selection procedure was employed to create resistant A2780 ovarian cancer cell sublines.
- Characterization of platinum drug accumulation, cross-resistance patterns, and potential resistance mechanisms (e.g., transporter expression, drug inactivation).
Main Results:
- A cisplatin-resistant subline (A2780-Pt) was established, exhibiting significantly reduced cisplatin accumulation and a resistance factor of 8.6.
- A2780-Pt cells showed cross-resistance to carboplatin, tetraplatin, and oxaliplatin, linked to decreased platinum accumulation.
- Resistance was not attributed to altered expression of key transporters (MRP2, CTR1, ATP7A/B), metallothionein, or glutathione, nor altered platinum efflux.
- Impaired platinum influx, specific to cis-configured platinum compounds, was identified as the likely cause of resistance, suggesting a defect in a specific inward transporter.
Conclusions:
- A stable cisplatin-resistant ovarian cancer cell line (A2780-Pt) was successfully generated.
- The findings suggest a novel mechanism of platinum resistance involving an impaired inward transporter specific for cis-platinum drugs.
- This A2780-Pt model provides a valuable tool for further research into platinum resistance and the development of strategies to overcome it.
Related Concept Videos
01:16Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
01:06Carrier-Mediated Transport
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...