Khurana Ashwani, Roy Debarshi, Kalogera Eleftheria, Mondal Susmita, Wen Xuyang, He Xiaoping, Dowdy Sean, Shridhar Viji
Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Oncotarget. 2015 Nov 3;6(34):36354-69. doi: 10.18632/oncotarget.5632.
A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cells compared to their isogenic chemosensitive control cells as quantified by the Chou-Talalay methodology. Our preliminary data, in vitro and in vivo, indicate that QC induces autophagy by downregulating p62/SQSTM1 to sensitize chemoresistant cells to autophagic- and caspase-mediated cell death in a p53-independent manner. QC promotes autophagosome accumulation and enhances autophagic flux by clearance of p62 in chemoresistant ovarain cancer (OvCa) cell lines to a greater extent compared to their chemosensitive controls. Notably, p62 levels were elevated in chemoresistant OvCa cell lines and knockdown of p62 in these cells resulted in a greater response to QC treatment. Bafilomycin A, an autophagy inhibitor, restored p62 levels and reversed QC-mediated cell death and thus chemosensitization. Importantly, our in vivo data shows that QC alone and in combination with carboplatin suppresses tumor growth and ascites in the highly chemoresistant HeyA8MDR OvCa model compared to carboplatin treatment alone. Collectively, our preclinical data suggest that QC in combination with carboplatin can be an effective treatment for patients with chemoresistant OvCa.
一种有前景的癌症治疗新策略是靶向自噬途径。在本研究中，我们证明，与通过Chou-Talalay方法定量的同基因化疗敏感对照细胞相比，抗疟药物奎纳克林（QC）以自噬依赖性方式更广泛地降低了化疗耐药细胞的细胞活力，并促进了化疗诱导的细胞死亡。我们的体外和体内初步数据表明，QC通过下调p62/SQSTM1诱导自噬，以p53非依赖性方式使化疗耐药细胞对自噬和半胱天冬酶介导的细胞死亡敏感。与化疗敏感对照相比，QC在化疗耐药的卵巢癌（OvCa）细胞系中通过清除p62更显著地促进自噬体积累并增强自噬通量。值得注意的是，化疗耐药的OvCa细胞系中p62水平升高，在这些细胞中敲低p62导致对QC治疗的反应更大。自噬抑制剂巴弗洛霉素A恢复了p62水平，并逆转了QC介导的细胞死亡，从而逆转了化疗增敏作用。重要的是，我们的体内数据表明，与单独使用卡铂治疗相比，QC单独使用以及与卡铂联合使用可抑制高度化疗耐药的HeyA8MDR OvCa模型中的肿瘤生长和腹水。总体而言，我们的临床前数据表明，QC与卡铂联合使用可能是化疗耐药OvCa患者的有效治疗方法。
