title: The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair.
abstract: Triple negative breast cancer (TNBC), characterized by an abundance of treatment-resistant breast cancer stem cells (CSCs), has a poorer prognosis than other types of breast cancers. Despite its aggressiveness, no effective targeted therapy exists for TNBC. Here, we demonstrate that CQ effectively targets CSCs via autophagy inhibition, mitochondrial structural damage, and impairment of double-stranded DNA break repair. Electron microscopy demonstrates CQ-induced mitochondrial cristae damage, which leads to mitochondrial membrane depolarization with a significant reduction in the activity of cytochrome c oxidase and accumulation of superoxide and double-stranded DNA breaks. CQ effectively diminishes the TNBC cells' ability to metastasize in vitro and in a TNBC xenograft model. When administered in combination with carboplatin, CQ effectively inhibits carboplatin-induced autophagy. This combination treatment significantly diminishes the expression of DNA repair proteins in CSC subpopulations, resulting in tumor growth reduction in carboplatin-resistant BRCA1 wild-type TNBC orthotopic xenografts. As TNBC's high treatment failure rate has been attributed to enrichment of CSCs, CQ, an autophagy inhibitor with anti-CSC effects, may be an effective adjunct to current TNBC chemotherapy regimens with carboplatin.
authors.affiliation: Department of Surgery, Houston Methodist Hospital, 6550 Fannin St., Smith Tower 1661, Houston, TX 77030, United States; Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, United States.
authors.forename: Diana H
authors.initials: DH
authors.lastname: Liang
authors.affiliation: Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, United States; Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main St., OPC 24, Houston, TX 77030, United States.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Choi
authors.affiliation: Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, United States; Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main St., OPC 24, Houston, TX 77030, United States.
authors.forename: Joe E
authors.initials: JE
authors.lastname: Ensor
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza Mail Stop BCM225, Houston, TX 77030, United States.
authors.forename: Benny A
authors.initials: BA
authors.lastname: Kaipparettu
authors.affiliation: Department of Surgery, Houston Methodist Hospital, 6550 Fannin St., Smith Tower 1661, Houston, TX 77030, United States.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Bass
authors.affiliation: Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, United States; Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main St., OPC 24, Houston, TX 77030, United States. Electronic address: jcchang@houstonmethodist.org.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D013481:Superoxides; D002738:Chloroquine; D016190:Carboplatin; D003576:Electron Transport Complex IV
keywords: Breast cancer stem cells; Chloroquine; Mitochondrial damage; Oxidative stress