Fibrates in the chemical action of daunorubicin

Abstract

Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves DNA damage caused by inhibition of topoisomerase II. Enzymatic detoxification of anthracycline is a major critical factor that determines anthracycline resistance. Natural product, daunorubicin a toxic analogue of anthracycline is reduced to less toxic daunorubicinol by the AKR1B10, enzyme, which is overexpressed in most cases of smoking associate squamous cell carcinoma (SCC) and adenocarcinoma. In addition, AKR1B10 was discovered as an enzyme overexpressed in human liver, cervical and endometrial cancer cases in samples from uterine cancer patients. Also, the expression of AKR1B10 was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma in cervical cancer and estimated to have the potential as a tumor intervention target colorectal cancer cells (HCT-8) and diagnostic marker for non-small-cell lung cancer. This article presents the mechanism of daunorubicin action and a method to improve the effectiveness of daunorubicin by modulating the activity of AKR1B10.

Fig. (1).

AKR1B10 catalyzed reduction of daunorubicin. Ketone moiety in the tetracyclic ring is converted to alcohol in the presence of NADPH.

Fig. (2).

Binding of daunorubicin in the active site cavity of AKR1B10. Active site of AKR1B10 is shown in the surface representation and color corded in white, red and blue to reflect the neutral, negative and positive residues. Nicotinamide ring of the cofactor in yellow and the daunorubicin in white are presented with N and O atoms in blue and red respectively.

Fig. (3).

Chemical structures of the inhibitors capable of modulating AKR1B10 catalyzed inactivation of daunorubicin reaction. Ciprofibrate for 2-[p-(2,2-dichlorocyclopropyl)-phenoxy]-2-methylpropanoic acid, Fenofibrate for the isopropyl ester of 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid, Fenofibric acid for 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid and Wy 14,643 for 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.