Main Organiser

Julius Centre University of Malaya

Co-organiser

Department of Social and Preventive Medicine, Faculty of Medicine, University of Malay

Supported by

University of Malaya

ANTITUMOR EFFECTS OF NOVEL QUINUCLIDINONE DERIVATIVE AGAINST BREAST CANCER

Author

Ahmed Malki

Institution

Biochemistry Department, Faculty of Science, Alexandria University, Alexandria Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University

Abstract

Objectives: Novel quinuclidinone derivatives have been previously reported by our laboratory, in this study we synthesized two novel quinuclidinone derivatives 4 and 6 to be tested in breast cancer cells (MCF-7) and their normal counterparts (MCF- 12a). Additionally, we investigated the impact of the potent derivative on survival and apoptotic signals.

Methods: The effects of our derivative were investigated by MTT assay, sphingomylinase activity, ELISA based apoptotic assay, TUNEL assay, immunofluoresence staining, flow cytometry, real time RT-PCR, western blot analysis and molecular modeling studies

Results: Our data indicated that derivatives 4 and 6 reduced proliferation and induced apoptosis in breast cancer cells. However, derivative 6 was less cytotoxic to normal breast epithelial cells than breast cancer cells; therefore, we focused on derivative 6 for further investigation. Flow cytometric analysis showed that quinuclidinone derivative 6 reduced the percent of MCF-7 cells in G2/M which is confirmed by increased expression levels of cyclin B while it arrests MCF12a in G1 phase judging from increased p21. Quinuclidinone derivative 6 also increased expression level of p53 and reduced expression level of Mdm2, it also increased expression level of bax at both protein and mRNA levels. Molecular modeling studies confirmed interactions between quinuclidinone derivative 6 and sphingomyelinase and provide understandable evidence for the observed anti- cancer behavior.

Conclusion: All these results confirm that our quinuclidinonee derivative 6 induces apoptosis in bresat cancer cells and our In vivo studies reveal that quinuclidinone derivative 6 does not induce any apparent toxicity and seems to be a promising candidate for further anticancer investigations.