title: Quinacrine has anticancer activity in breast cancer cells through inhibition of topoisomerase activity.
abstract: The small molecule Quinacrine (QC, a derivative of 9-aminoacridine), an anti-malaria drug, displays activity against cancer cell lines and can simultaneously suppress nuclear factor-κB (NF-κB) and activate p53 signaling. In this study, we investigated the anticancer mechanism underlying these drug activities in breast cancer cell lines. QC caused a dose-dependent decrease of both anchorage dependent and independent growth of breast cancer cells (MCF-7 and MDA-MB-231) without affecting normal breast epithelial cells (MCF-10A), as evident from clonogenic cell survival, [3-(4,5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide] viability, wound healing and soft agar growth. QC activated the proapoptotic marker Bax, PARP cleavage, p53 and its downstream target, p21 (Cip1/Waf1) and downregulated the antiapoptotic marker Bcl-xL and relative luciferase activity of NF-κB in MCF-7 cells. Results of DAPI nuclear staining and FACS analysis show that QC increased apoptosis in a dose-dependent manner. QC caused apoptosis by increasing the cell population in S-phase and simultaneously decreasing the G1 and G2/M populations. A dose-dependent increase of DNA damage as measured by the comet assay was seen in MCF-7 cells after exposure to QC. With regards to the mechanism of DNA damage, we found that QC inhibited topoisomerase activity in MCF-7 cells by increasing the unwinding of supercoiled DNA. Collectively, the results demonstrate that QC has efficient anticancer potential against breast cancer cells via not only an induction of p53 and p21 but also an induction of S phase arrest, DNA damage and inhibition of topoisomerase activity.
authors.affiliation: KIIT School of Biotechnology, KIIT University, Patia, Bhubaneswar, Orissa, India.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Preet
authors.forename: Purusottam
authors.initials: P
authors.lastname: Mohapatra
authors.forename: Suchitra
authors.initials: S
authors.lastname: Mohanty
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Sahu
authors.forename: Tathagata
authors.initials: T
authors.lastname: Choudhuri
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wyatt
authors.forename: Chanakya Nath
authors.initials: CN
authors.lastname: Kundu
mesh_terms: D000328:Adult; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D026942:DNA Topoisomerases / Q000378:metabolism*; D004278:DNA, Superhelical / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology*; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004278:DNA, Superhelical; D016328:NF-kappa B; D059003:Topoisomerase Inhibitors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D026942:DNA Topoisomerases; D011796:Quinacrine