title: In vitro and in vivo efficacy of a novel quinuclidinone derivative against breast cancer.
abstract: Previously, our laboratory reported on novel quinuclidinone derivatives that cause cytotoxicity in human non-small lung carcinoma epithelial cells null for p53 (H1299). The current study aims to investigate the effect of novel designed quinuclidinone derivatives on cytotoxicity towards human MCF-7 breast cancer cells, normal breast epithelial cells (MCF-12a) and an animal model of breast cancer. Quinuclidinone 2 induced growth inhibition mainly through apoptosis in breast cancer cells (MCF-7), with less cytotoxic effects towards normal breast epithelial cells (MCF-12a) compared to the other derivatives. Our novel quinuclidinone-2 increased expression of p53 and cyclin-D and reduced expression levels of (Mdm2), (Bcl-2) and (Akt). It also reduced expression of (Bax) as down stream target of p53 at both RNA and protein levels. Additionally, quinuclidinone 2 induced G1 phase arrest presumably sensitizing breast cancer cells to apoptosis by increasing expression of p21. In vivo studies were performed to assess the anticancer effect of quinuclidinone 2 on N-Nitroso-N-methylurea-induced breast cancer in female rats by evaluating physiological processes and the expression levels of β-catenin and E-cadherin. The approximate lethal dose of quinuclidinone 2 was determined to be 90 mg/kg and it led to significant reduction in tumor size compared to the untreated group. In vivo studies revealed that quninuclidinone derivative 6 does not induce any apparent toxicity towards the treated hosts and under the present experimental set up seems to be a promising candidate for further evaluation in cancer therapy.
authors.affiliation: Department of Health Sciences, Biomedical Sciences Program, Faculty of Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar. ahmed.malki@qu.edu.qa.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.forename: El Sayed
authors.initials: el S
authors.lastname: El Ashry
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008770:Methylnitrosourea / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D011812:Quinuclidines; D008770:Methylnitrosourea
keywords: Anticancer drugs; Bax; E-Cadherin; breast cancer; cell cycle; p21; p53