title: Molecular trail for the anticancer behavior of a novel copper carbohydrazone complex in BRCA1 mutated breast cancer.
abstract: Novel chelated metal complexes were synthesized from carbohydrazones to thiocarbohydrazones using metal-based drug designing platforms and their combination effect with Pb, a naphthaquinone were analyzed for anticancer activity in breast cancer cell lines. A panel of BRCA1 wild-type and mutated breast cancer cells: MCF-7 (BRCA1+/ER+), MDA-MB-231 (BRCA1+/ERα-), HCC-1937 (BRCA1-/ERα-), HCC1937/wt BRCA1, MX1 (BRCA1-/ERα-), and MDA-MB-436 (BRCA1-/ERα-) were screened for anti-cancer activity. Cu2(HL)(HSO4) · H2O]SO4· 6 H2O (CS2) is the most potent anticancer agent among the copper carbohydrazone and thiocarbohydrazone complexes analyzed in this study. It can be suggested that the presence of sulphate, as pharmacologically active centre, can induce cytotoxicity more effectively when compared to chlorine, bromine, perchlorate, and methanol. This is the first report demonstrating that CS2 can bind to DNA by hindering BamH1 activity and could induce DNA double strand breaks as evidenced by γ-H2AX expression. In addition to this, CS2 could also act as a Topo II inhibitor at a much lower concentration than etoposide and induce apoptosis, making it a potent anticancer agent. In combination with Pb, a potent ROS inducer, CS2 could induce synergistic anti-cancer activity in HR/ BRCA1 defective breast cancer cells. This is the first study reporting the mechanism involved in the induction of apoptosis for a metal chelated copper carbohydrazone complex and its combination effects with Pb in HR defective, BRCA1 mutated breast cancer cells.
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud, Thiruvananthapuram, Kerala, India.
authors.forename: Rakesh Sathish
authors.initials: RS
authors.lastname: Nair
authors.affiliation: Department of Applied Chemistry, Cochin University of Science and Technology, Kochin, Kerala, India.
authors.forename: Manoj Easwaran
authors.initials: ME
authors.lastname: Potti
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud, Thiruvananthapuram, Kerala, India.
authors.forename: Ratheeshkumar
authors.initials: R
authors.lastname: Thankappan
authors.affiliation: Bioinformatics Centre, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
authors.forename: Sivakumar Krishnankutty
authors.initials: SK
authors.lastname: Chandrika
authors.affiliation: Department of Applied Chemistry, Cochin University of Science and Technology, Kochin, Kerala, India.
authors.forename: M R Prathapachandra
authors.initials: MR
authors.lastname: Kurup
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud, Thiruvananthapuram, Kerala, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Srinivas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology; D016513:Mice, SCID; D009154:Mutation; D009285:Naphthoquinones / Q000008:administration & dosage / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004273:DNA, Neoplasm; D006835:Hydrazones; D009285:Naphthoquinones; D009942:Organometallic Compounds; D059005:Topoisomerase II Inhibitors; D003300:Copper; C014758:plumbagin
keywords: DNA damage; anticancer activity; copper carbohydrazone complex; plumbagin