Inhibition of Abcg2 transporter on primitive hematopoietic stem cells by All-trans retinoic acid increases sensitivity to anthracycline

It is well established that All-trans retinoic acid (RA) regulates the growth and differentiation of a wide variety of tissues and cell types. Here we found that RA has a new role, the breast cancer resistance protein (Abcg2) inhibitor. RA, like the transporter inhibiter reserpine, dose-dependently reduced the efflux of Hoechst dye from HSCs by inhibiting the Abcg2 transporter without requiring new transcription. The effects of RA and reserpine on the SP were reversible upon wash-out. Similar results were obtained in NIH3T3-GFP cells stably expressing Abcg2. RA-treated and Abcg2-deficient HSCs showed increased sensitivity to doxorubicin, a type of anthracycline. Our evidence suggests that, besides playing crucial roles in the survival, growth, and differentiation of HSCs, RA has a novel function as an inhibitor of the Abcg2 transporter.