A Pharmacological Strategy Using Stemofoline for more Efficacious Chemotherapeutic Treatments Against Human Multidrug Resistant Leukemic Cells

Abstract

Our previous study reported that stemofoline (STF) exhibited a synergistic effect with chemotherapeutic drugs in<br />human multidrug-resistant (MDR) leukemic cells (K526/Adr) by inhibiting the function of P-glycoprotein, which is a<br />membrane transporter that is overexpressed in several types of MDR cancers. This study further investigated the effects of<br />a combination treatment of STF and doxorubicin (DOX) in vitro and in vivo. The combination treatment of 50 mg/kg of<br />STF strongly enhanced the anti-tumor activity of DOX in SCID-beige mice bearing K562/Adr xenografts without<br />additional toxicity when compared to the single treatment groups. Additionally, an examination of the proliferation<br />markers (Ki67) and the apoptotic marker (TUNEL) in tumor tissues in each group revealed that the combination<br />therapy significantly reduced Ki67 positive cells and increased apoptotic cells. From the in vitro experiments we also<br />found that this combination treatment dramatically induced G1 and G2M arrest in K562/Adr when compared to a single<br />treatment of DOX. STF treatment alone did not show any cytotoxic effect to the cells. These results suggest that the<br />accumulation of DOX enhanced by STF was sufficient to induce cell cycle arrest in K562/Adr. These findings support<br />our previous in vitro data and indicate the possibility of developing STF as an adjuvant therapy in cancer treatments.