The Effect of Chemotherapeutic Agents Used in Breast Cancer Treatment on the Hepatic Lipotoxicity.

Abstract

Breast cancer (BC) is the most common type of cancer in women. Researchers have studied various types of inhibitors of the MAPK/ERK signaling pathway, which plays an important role in the growth of BC cells. PD98059 is a potent and selective inhibitor of MEK, which may have potential application in the combined treatment of BC along with doxorubicin and Taxotere. The aim of this study was to provide a new insight into hepatotoxicity caused by doxorubicin, Taxotere, and PD98059 mono/combination therapy in a hepatoma in vitro model. HepG2 cells were treated with appropriate doses of used drugs. The expression of FASN and SCD1 lipogenic genes was measured by real-time PCR. The fatty acid composition PL and triglyceride fractions were analyzed using gas-liquid chromatography. The indicators of oxidative stress and antioxidant defense systems were measured by the calorimetric method. Doxorubicin and Taxotere significantly decreased FASN expression and increased SCD1 expression. Additionally, the combination of PD98059 alone, in combination with doxorubicin, or doxorubicin and Taxotere significantly increased the expression of SCD1. However, the combination of PD98059 and Taxotere significantly decreased this expression. PD98059 alone also dramatically increased the expression of FASN. In the PL fraction, doxorubicin, Taxotere, or PD98059 increased the percentage of saturated fatty acids and decreased the relative amount of unsaturated fatty acids alone. The doxorubicin + PD98059 combination also enhanced the effect of doxorubicin on PL SFAs and UFAs. Taxotere also reduced the SFAs and increased UFAs in the triglyceride fraction, which was also neutralized by PD98059 addition. Based on these findings, increased expression of SCD1 and elevated levels of SFAs in lipid fractions may indicate the possibility of hepatic lipotoxicity in BC patients, which necessitates the narrow monitoring of steatohepatitis in these patients.