title: Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway.
abstract: Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent.
authors.affiliation: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Mail Code 6610, P. O. Box 9515, Jeddah, 21423, Kingdom of Saudi Arabia. salehay@ksau-hs.edu.sa.|King Abdullah International Medical Research Center (KAIMRC), P. O. Box 9515, Jeddah, 21423, Kingdom of Saudi Arabia. salehay@ksau-hs.edu.sa.
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Saleh
authors.affiliation: King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, P.O. Box 22490, Riyadh, 11426, Kingdom of Saudi Arabia.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Aziz
authors.affiliation: Department of Chemistry, Faculty of Sciences, United Arab Emirates University, P. O. Box 15551, Al-Ain, United Arab Emirates.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Abdou
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
authors.affiliation: Department of Chemistry, Faculty of Sciences, Yarmouk University, Irbid, 21163, Jordan.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Al-Qudah
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah Almonawarrah, 41477, Saudi Arabia.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Abadleh
authors.affiliation: King Abdullah International Medical Research Center (KAIMRC), P. O. Box 9515, Jeddah, 21423, Kingdom of Saudi Arabia.|Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, 11481, Kingdom of Saudi Arabia.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Aljada
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, FL, 33328, USA.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Rizvi
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D018922:HL-60 Cells; D006571:Heterocyclic Compounds / Q000633:toxicity*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D020169:Caspases
keywords: Anti-cancer; Apoptosis; Bax; Bcl-2; Heterocyclic pyrazole N-nucleosides; Mitochondria dysfunction; ROS