title: Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells.
abstract: The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.
authors: Maryam
authors: M
authors: Zahedifard
authors: Fadhil Lafta
authors: FL
authors: Faraj
authors: Mohammadjavad
authors: M
authors: Paydar
authors: Chung Yeng
authors: CY
authors: Looi
authors: Pouya
authors: P
authors: Hasandarvish
authors: Maryam
authors: M
authors: Hajrezaie
authors: Behnam
authors: B
authors: Kamalidehghan
authors: Nazia Abdul
authors: NA
authors: Majid
authors: Shaden A M
authors: SA
authors: Khalifa
authors: Hapipah Mohd
authors: HM
authors: Ali
authors: Mahmood Ameen
authors: MA
authors: Abdulla
authors: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia, Department of Experimental Hematology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden; Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75 123, Uppsala, Sweden. hesham.el-seedi@fkog.uu.se.
authors: Hesham R
authors: HR
authors: El-Seedi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D020169:Caspases