title: Chk1 inhibitor synergizes quinacrine mediated apoptosis in breast cancer cells by compromising the base excision repair cascade.
abstract: Quinacrine (QC) causes apoptosis in breast cancer cells by induction of DNA damage, arrest of cells in S-phase, and by topoisomerase inhibition. Here, we show that QC-mediated apoptosis is not only due to increased DNA damage but also by compromising cell cycle checkpoints and base excision repair (BER) capacity in breast cancer cells. QC decreased CHK1, CDKs (CDC2, MDM2, CDC6), cyclins (B1, E1) and CDC25-A in a dose dependent manner. The expression of basal ATR remains unaltered but pATR (Ser-428) increased after QC treatment. A CHK1 inhibitor, SB218078, was also tested alone and in combination with QC. Like QC, SB218078 caused apoptosis by DNA damage and S-phase arrest. The combination of QC and SB218078 increased apoptosis by blocking the cell cycle in G2/M, which caused a mitotic catastrophe, and induced DNA damage at a higher level in comparison to individual compound treatments. Both drugs individually or in combination decreased the levels of replication protein A (RPA). Measurement of the expression of BER (SP- and LP-BER) proteins and direct in vivo BER activity revealed that the QC/SB218078 combination caused apoptosis in cancer cells by disrupting the induction of BER, which represents a novel means of potentially treating breast cancer.
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
authors: Ranjan
authors: R
authors: Preet
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
authors: Sumit
authors: S
authors: Siddharth
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
authors: Shakti Ranjan
authors: SR
authors: Satapathy
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
authors: Sarita
authors: S
authors: Das
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
authors: Anmada
authors: A
authors: Nayak
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
authors: Dipon
authors: D
authors: Das
authors: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.
authors: Michael D
authors: MD
authors: Wyatt
authors: Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India. Electronic address: cnkundu@gmail.com.
authors: Chanakya Nath
authors: CN
authors: Kundu
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000071877:Checkpoint Kinase 1; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D011796:Quinacrine; C404329:SB 218078
keywords: 9-Aminoacridine; Base-excision repair; Breast cancer; CHK1; Quinacrine