title: Monobenzyltin Complex C1 Induces Apoptosis in MCF-7 Breast Cancer Cells through the Intrinsic Signaling Pathway and through the Targeting of MCF-7-Derived Breast Cancer Stem Cells via the Wnt/β-Catenin Signaling Pathway.
abstract: Monobenzyltin Schiff base complex, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, C1, is an organotin non-platinum metal-based agent. The present study was conducted to investigate its effects on MCF-7 cells with respect to the induction of apoptosis and its inhibitory effect against MCF-7 breast cancer stem cells. As determined in a previous study, compound C1 revealed strong antiproliferative activity on MCF-7 cells with an IC50 value of 2.5 μg/mL. Annexin V/propidium iodide staining coupled with flow cytometry indicated the induction of apoptosis in treated cells. Compound C1 induced apoptosis in MCF-7 cells and was mediated through the intrinsic pathway with a reduction in mitochondrial membrane potential and mitochondrial cytochrome c release to cytosol. Complex C1 activated caspase 9 as a result of cytochrome c release. Subsequently, western blot and real time PCR revealed a significant increase in Bax and Bad expression and a significant decrease in the expression levels of Bcl2 and HSP70. Furthermore, a flow cytometric analysis showed that treatment with compound C1 caused a significant arrest of MCF-7 cells in G0/G1 phase. The inhibitory analysis of compound C1 against derived MCF-7 stem cells showed a significant reduction in the aldehyde dehydrogenase-positive cell population and a significant reduction in the population of MCF-7 cancer stem cells in primary, secondary, and tertiary mammospheres. Moreover, treatment with C1 down-regulated the Wnt/β-catenin self-renewal pathway. These findings indicate that complex C1 is a suppressive agent of MCF-7 cells that functions through the induction of apoptosis, cell cycle arrest, and the targeting of MCF-7-derived cancer stem cells. This work may lead to a better treatment strategy for the reduction of breast cancer recurrence.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Somayeh
authors.initials: S
authors.lastname: Fani
authors.affiliation: Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, 14174 Tehran, Iran.|Department of Exercise Science, Sports Center, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Dehghan
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Hamed
authors.initials: H
authors.lastname: Karimian
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Kong
authors.initials: K
authors.lastname: Mun Lo
authors.affiliation: Institute of Bioscience, University Putra Malaysia, 43400 Serdang, Malaysia.
authors.forename: Siyamak
authors.initials: S
authors.lastname: Ebrahimi Nigjeh
authors.affiliation: Institute of Bioscience, University Putra Malaysia, 43400 Serdang, Malaysia.
authors.forename: Yeap
authors.initials: Y
authors.lastname: Swee Keong
authors.affiliation: Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, 14174 Tehran, Iran.
authors.forename: Rahman
authors.initials: R
authors.lastname: Soori
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Kit
authors.initials: K
authors.lastname: May Chow
authors.affiliation: Medical Genetics Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran-Karaj Highway, Tehran, Iran.
authors.forename: Behnam
authors.initials: B
authors.lastname: Kamalidehghan
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.|Center for Natural Products and Drug Discovery (CENAR), Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Hapipah
authors.initials: H
authors.lastname: Mohd Ali
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.|Center for Natural Products and Drug Discovery (CENAR), Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Najihah
authors.initials: N
authors.lastname: Mohd Hashim
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D000066673:Cell Self Renewal / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D014001:Tin / Q000737:chemistry*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D010718:Phosphatidylserines; D014001:Tin; D045304:Cytochromes c; D000444:Aldehyde Dehydrogenase; D053179:Caspase 7; D053453:Caspase 9