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MDR1 inhibition increases sensitivity to doxorubicin and etoposide in adrenocortical cancer
S G Creemers1, P M van Koetsveld1, W W De Herder1
1Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Abstract:
Chemotherapy for adrenocortical carcinoma (ACC) has limited efficacy and is accompanied by severe toxicity. This lack of effectiveness has been associated with high tumoral levels of the multidrug resistance (MDR) pump P-glycoprotein (P-gp), encoded by the MDR1 gene. In this study, effects of P-gp inhibition on the sensitivity of ACC cells to cytotoxic drugs were evaluated. MDR1 mRNA and P-gp expression were determined in human adrenal tissues and cell lines. H295R, HAC15 and SW13 cells were treated with mitotane, doxorubicin, etoposide, cisplatin and streptozotocin, with or without the P-gp inhibitors verapamil and tariquidar. Cell growth and surviving fraction of colonies were assessed. MDR1 mRNA and P-gp protein expression were lower in ACCs than in adrenocortical adenomas (P < 0.0001; P < 0.01, respectively). MDR1 and P-gp expression were positively correlated in ACC (P < 0.0001, ρ = 0.723). Mitotane, doxorubicin, cisplatin and etoposide dose dependently inhibited cell growth in H295R, HAC15 and SW13. Tariquidar, and in H295R also verapamil, increased the response of HAC15 and H295R to doxorubicin (6.3- and 7.5-fold EC50 decrease in H295R, respectively; all P < 0.0001). Sensitivity to etoposide was increased in H295R and HAC15 by verapamil and tariquidar (all P < 0.0001). Findings were confirmed when assessing colony formation. We show that cytotoxic drugs, except streptozotocin, used for ACC treatment, inhibit ACC cell growth and colony formation at clinically achievable concentrations. P-gp inhibition increases sensitivity to doxorubicin and etoposide, suggesting that MDR1 is involved in sensitivity to these drugs and could be a potential target for cytotoxic treatment improvement in ACC.
Insights
Adrenocortical carcinoma (ACC) chemotherapy is often ineffective due to P-glycoprotein (P-gp). Inhibiting P-gp enhances ACC cell sensitivity to drugs like doxorubicin and etoposide, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy for adrenocortical carcinoma (ACC) exhibits limited efficacy and significant toxicity.
- High tumoral levels of P-glycoprotein (P-gp), encoded by the MDR1 gene, are associated with this reduced effectiveness.
- P-gp acts as a multidrug resistance (MDR) pump, limiting the intracellular concentration of cytotoxic drugs.
Purpose of the Study:
- To evaluate the effects of P-gp inhibition on the sensitivity of ACC cells to various cytotoxic drugs.
- To investigate the role of MDR1 gene expression and P-gp protein levels in ACC drug resistance.
- To identify potential therapeutic strategies for improving ACC treatment outcomes.
Main Methods:
- MDR1 mRNA and P-gp protein expression were quantified in human adrenal tissues and ACC cell lines (H295R, HAC15, SW13).
- ACC cells were treated with mitotane, doxorubicin, etoposide, cisplatin, and streptozotocin, with or without P-gp inhibitors (verapamil, tariquidar).
- Cell growth inhibition and colony formation assays were performed to assess drug sensitivity.
Main Results:
- MDR1 mRNA and P-gp protein expression were significantly lower in adrenocortical adenomas compared to ACCs.
- P-gp inhibition, using verapamil and tariquidar, significantly increased ACC cell sensitivity to doxorubicin and etoposide.
- Cytotoxic drugs, excluding streptozotocin, demonstrated dose-dependent inhibition of ACC cell growth and colony formation.
Conclusions:
- MDR1 and P-gp expression are implicated in the drug resistance observed in adrenocortical carcinoma.
- P-gp inhibition represents a promising strategy to enhance the efficacy of doxorubicin and etoposide in ACC treatment.
- Targeting P-gp could represent a valuable approach for improving cytotoxic therapy in adrenocortical carcinoma.
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