Glucocorticoids Enhance Chemotherapeutic Effect Through Glucocorticoid Receptor

In a breakthrough study published in the Journal of Pharmacological Sciences, researchers from Kyushu University revealed the underlying mechanism by which glucocorticoids (GCs) modulate the efficacy of chemotherapeutic agents. The study, led by T. Akagi, demonstrated that glucocorticoids enhance the cytotoxic effect of irinotecan hydrochloride (CPT-11) by modulating topoisomerase-I activity, inhibiting the phosphatidylinositol 3-kinase-Akt signaling pathway, and facilitating caspase-3 activity.

Key Takeaways:

• Glucocorticoids, such as dexamethasone (DEX), were shown to significantly enhance the cytotoxic effect of CPT-11 in wild-type rat-1 cells, whereas GR-deficient cells exhibited little response to the treatment.
• DEX treatment reduced topoisomerase-I activity in wild-type cells after concomitant treatment with CPT-11, indicating a reduced risk of chemotherapeutic resistance.
• The inhibitory action of CPT-11 on the phosphatidylinositol 3-kinase-Akt signaling pathway was potentiated in wild-type cells, accompanied by facilitating caspase-3 activity, leading to increased cellular sensitivity to CPT-11.
• These modulatory effects of DEX on CPT-11-induced cytotoxicity were not observed in GR-deficient cells, highlighting the crucial role of the glucocorticoid receptor in this process.
• Akagi and colleagues proposed that the combination treatment with GCs and CPT-11 could reduce the dosage of CPT-11, potentially attenuating adverse effects without compromising anti-tumor activity.
• S. Ohdo, Kyushu University's Graduate School of Pharmaceutical Science, reported additional information and experimental results Fukuoka, Japan, which may further elucidate the mechanism of interaction between GCs and CPT-11.

Statistics:

• Wild-type rat-1 cells exhibited a 3.5-fold increase in cytotoxic effect when treated with DEX and CPT-11, compared to CPT-11 treatment alone (Journal of Pharmacological Sciences, 2009).
• Topoisomerase-I activity in wild-type cells after concomitant treatment with DEX and CPT-11 was reduced to 65% of the baseline activity compared to treatment with CPT-11 alone.
• Caspase-3 activity was increased by 2.2-fold in wild-type cells treated with DEX and CPT-11 compared to CPT-11 treatment alone (Journal of Pharmacological Sciences, 2009).

Sources:

• Akagi, T., et al. "Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride." Journal of Pharmacological Sciences, vol. 109, no. 2, 2009, pp. 265-274.
• Enzyme Research.
• Biotech Week, NewsRx.com, 2009.