title: ABT-888 and quinacrine induced apoptosis in metastatic breast cancer stem cells by inhibiting base excision repair via adenomatous polyposis coli.
abstract: PARP inhibitors in combination with other agents are in clinical trial against cancer, but its effect on cancer stem cells (CSCs) is limited. CSCs are responsible for drug resistance, metastasis and cancer relapse due to high DNA repair capacity. Here, we present preclinical effects of Quinacrine (QC) with ABT-888, a PARP inhibitor, on highly metastatic breast cancer stem cells (mBCSCs). An increased level of Adenomatous polyposis coli (APC) was noted after treatment with ABT-888 in QC pre-treated mBCSCs cells. Increased APC physically interacts with PARP-1 and inhibits PARylation causing the non assembly of base excision repair (BER) multiprotein complex, resulting in an irreparable DNA damage and subsequent apoptosis. Knockdown of APC in mBCSCs inhibited DNA damage, increased BER and PARylation, reduces apoptosis while the over-expression of APC in BT20 (APC low expressing) cells reversed the effect. Thus, combination of QC and ABT-888 decreased mBCSCs growth by activating APC and inhibiting BER within the cells.
authors.affiliation: Cancer Biology Division, School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Siddharth
authors.affiliation: Cancer Biology Division, School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
authors.forename: Deepika
authors.initials: D
authors.lastname: Nayak
authors.affiliation: Cancer Biology Division, School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
authors.forename: Anmada
authors.initials: A
authors.lastname: Nayak
authors.affiliation: Cancer Biology Division, School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
authors.forename: Sarita
authors.initials: S
authors.lastname: Das
authors.affiliation: Cancer Biology Division, School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India. Electronic address: cnkundu@gmail.com.
authors.forename: Chanakya Nath
authors.initials: CN
authors.lastname: Kundu
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011796:Quinacrine / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C521013:veliparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011796:Quinacrine
keywords: ABT-888; APC; Cancer stem cells; PARP inhibitor; Quinacrine