cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population吸烟促进耐药性和扩张的癌症干细胞的人口.pdfVIP

Cigarette Smoke Promotes Drug Resistance and Expansion of Cancer Stem Cell-Like Side Population 1. 1. 1 1 1 1 Yi An , Alan Kiang , Jay Patrick Lopez , Selena Z. Kuo , Michael Andrew Yu , Eric L. Abhold , 1 2 1 Jocelyn S. Chen , Jessica Wang-Rodriguez , Weg M. Ongkeko * 1 Division of Head and Neck Surgery, Department of Surgery, University of California San Diego, San Diego, California, United States of America, 2 Department of Pathology, School of Medicine, University of California San Diego, San Diego, California, United States of America Abstract It is well known that many patients continue to smoke cigarettes after being diagnosed with cancer. Although smoking cessation has typically been presumed to possess little therapeutic value for cancer, a growing body of evidence suggests that continued smoking is associated with reduced efficacy of treatment and a higher incidence of recurrence. We therefore investigated the effect of cigarette smoke condensate (CSC) on drug resistance in the lung cancer and head and neck cancer cell lines A549 and UMSCC-10B, respectively. Our results showed that CSC significantly increased the cellular efflux of doxorubicin and mitoxantrone. This was accompanied by membrane localization and increased expression of the multi- drug transporter ABCG2. The induced efflux of doxorubicin was reversed upon addition of the specific ABCG2 inhibitor Fumitremorgin C, confirming the role of ABCG2. Treatment with CSC increased the concentration of phosphorylated Akt, while addition of the PI3K inhibitor LY294002 blocked doxorubicin extrusion, suggesting that Akt activation is req